Counteracting spontaneous transformation via overexpression of rate-limiting DNA base excision repair enzymes

Guido Frosina

DNA Repair Unit, Mutagenesis Laboratory, Istituto Nazionale Ricerca Cancro, Largo Rosanna Benzi no. 10, 16132 Genova, Italy

Email: gfrosina{at}hp380.ist.unige.it


    Abstract
 Top
 Abstract
 Introduction
 Spontaneous transformation in...
 How similar are spontaneous...
 Stimulating DNA repair of...
 Rate-limiting steps of BER
 Possible ways to stimulate...
 Concluding remarks
 References
 
DNA damage of endogenous origin may significantly contribute to human cancer. A major pathway involved in DNA repair of endogenous damage is DNA base excision repair (BER). BER is rather efficient in human cells but a certain amount of endogenous damage inevitably escapes mending and likely contributes to human carcinogenesis. Apart from some glycosylases that are particularly sluggish (e.g. 8-oxoG DNA glycosylase), recent work suggests that the general rate-limiting steps of BER may be trimming of 2-deoxyribose 5-phosphate in case the process is started by a monofunctional glycosylase or trimming of a 3'-blocking fragment, in case BER is started by a bifunctional glycosylase or in the case of single-strand breaks produced by free radical attack. Overexpression of the 5'-deoxyribophosphodiesterase (dRPase) domain of DNA polymerase ß, on the one hand, and of yeast APN1 protein, containing an efficient 3' repair activity, on the other, may lead to improved BER in mammals. The recently characterized S3 protein of Drosophila, containing both dRPase and 3'-trimming activities, could also be considered for overexpression studies. The possible protecting role of enhanced BER could be investigated in cultured rodent embryonic fibroblasts undergoing spontaneous transformation, a most interesting system that merits rediscovery.

Abbreviations: AP, abasic; BER, base excision repair; dRP, 2-deoxyribose 5-phosphate; dRPase, 5'-deoxyribophosphodiesterase; MEF, mouse embryonic fibroblast; MMS, methylmethanesulfonate; 8-oxoG, 8-oxo-7,8-dihydroguanine; PCNA, proliferating cell nuclear antigen; PNK, polynucleotide kinase; pol ß, DNA polymerase ß; ROI, reactive oxygen intermediate.


    Introduction
 Top
 Abstract
 Introduction
 Spontaneous transformation in...
 How similar are spontaneous...
 Stimulating DNA repair of...
 Rate-limiting steps of BER
 Possible ways to stimulate...
 Concluding remarks
 References
 
Most human cancers may be considered `spontaneous' in nature as no evident specific inducing agent is usually identified. Development of cancer is linked to a number of genetic alterations caused by both endogenous and exogenous factors (1). These alterations are continuously selected for improved proliferation according to a Darwinian process. This phenomenon is fortunately very long and development of frank malignancies may take decades. The very slow selection of the spontaneous cancer phenotype has always been a major hindrance to cancer research. The development of new strategies to counteract the phenomenon may take advantage of simpler and more convenient systems that mimic the in vivo process.

Most primary animal cells exhibit a limited lifespan in culture and eventually undergo senescence, during which time the cells cease to proliferate with resultant cell death (2). With varying frequency, especially dependent on the species of origin, a few cells survive the senescence crisis and acquire unlimited proliferative potential. At the same time, measurable in months, they also spontaneously become neoplastic, displaying an increasing capacity to grow in soft agar and induce tumors in nude mice. A number of comprehensive reviews on in vitro spontaneous transformation have been produced (38) and for a detailed description of the phenomenon we refer to them. Transformation of cultured rodent fibroblasts has been used until recently to assess the carcinogenic properties of various drugs and metabolites (9,10), but exploitation of this phenomenon to investigate new strategies to prevent or reverse the spontaneous cancer phenotype has declined. This is somewhat surprising given the important achievements that have been made in understanding the molecular changes that underlie spontaneous in vitro transformation and the parallels between this phenomenon and human carcinogenesis. We here propose making use of spontaneous in vitro transformation to investigate the possible protecting role of accelerated DNA base excision repair (BER), the main pathway that repairs endogenous damage in mammalian cells.


    Spontaneous transformation in rodent and human cells
 Top
 Abstract
 Introduction
 Spontaneous transformation in...
 How similar are spontaneous...
 Stimulating DNA repair of...
 Rate-limiting steps of BER
 Possible ways to stimulate...
 Concluding remarks
 References
 
When embryonic cells are taken from a mouse and placed in culture they usually divide a limited number of times (10–15 population doublings or 15–20 days), after which most cells die (3,11,12). Some cells survive this crisis and become immortal, i.e. capable of indefinite growth. Cells that survive the crisis and become immortal are relatively frequent in rodent cell cultures, with an immortalization rate of 1–10x10–6per cell per generation (13,14). Variants that survive the crisis display aneuploidy, chromosomal aberrations and mutations in a number of tumor suppressor genes (1518), thus indicating significant genotypic alterations, but still have very limited proliferation capacity and no ability to grow in soft agar or induce tumors in nude mice (19). Within a period measurable in months cells slowly acquire improved proliferation potential and a number of characteristics that are typical of neoplastic cells, i.e. increased colony forming ability, loss of contact inhibition, elevated saturation density and ability to grow in soft agar and to induce tumors in nude mice (3,4,6,8). The process clearly involves continuous selection. Spontaneous immortalization and transformation is more frequent in mice than in rats but can be considered a general feature of rodent cells (6).

Unlike rodents, spontaneous in vitro transformation of human or avian cells is a very rare event (20). Three cases of spontaneous transformation of human fibroblasts have been reported (2123), together with a few other cases with other cell types, such as epidermal keratinocytes (24) and mammary epithelial cells (25). Genuine derivation of transformed cells from normal diploid parent cells has even been questioned in some of the above cases (5). Spontaneous immortalization is more frequent in normal cells from patients with Li–Fraumeni syndrome who carry inherited mutations of the p53 gene (2628). It is clear that the combination of events that lead human fibroblasts to spontaneously immortalize and subsequently transform in culture is extremely rare in comparison with rodent cells. A possible explanation for this is that the number of mutational events required to confer immortality on human cells is higher than the number required for rodent cells (7,2931). For example, human fibroblasts control the number of cell divisions by telomere shortening, a mechanism that is not present in mice (32,33). Further, rates of spontaneous mutation are lower in humans (34). This may be linked to their higher repair capacity [demonstrated for nucleotide excision repair but probably applying to repair of endogenous damage as well] and slower metabolism (3537). As a consequence, no human cell can acquire a sufficient number of alterations necessary for indefinite growth before the onset of crisis.


    How similar are spontaneous transformation of cultured rodent cells and human carcinogenesis?
 Top
 Abstract
 Introduction
 Spontaneous transformation in...
 How similar are spontaneous...
 Stimulating DNA repair of...
 Rate-limiting steps of BER
 Possible ways to stimulate...
 Concluding remarks
 References
 
Spontaneous in vitro transformation of rodent cells resembles human carcinogenesis in some aspects. First, like most human cancers it occurs in the absence of any intentional or known treatment. Second, a major agent responsible for spontaneous malignant transformation of mouse embryonic fibroblasts (MEFs) is atmospheric oxygen (38). Lowering the concentration of oxygen from 18 to ~1% markedly reduces the phenomenon (38). Addition of catalase to the culture medium decreases the incidence of chromosomal aberrations and delays or prevents the onset of neoplastic transformation of mouse fibroblasts, thus indicating that H2O2 and/or the derivative OH are factors involved (39). The proliferative effect of superoxide radicals varies with the stage of neoplastic progression (40). Some indications point to a role of oxygen in human cancer too. More than 20 years ago it was observed in pioneering epidemiological studies that there is little contribution of industrialization and general pollution to the spontaneous rate of occurrence of cancer and that oxygen metabolism may play a role (41,42). Much subsequent evidence has confirmed this notion and has pointed to endogenous damage as a factor in the etiology of cancer, with particular reference to products of oxygen metabolism (reviewed in refs 43–46). A small but probably steady production of carcinogenic radicals is the price to be paid for aerobic metabolism. Third, the spontaneous transformation of MEFs is accompanied by inactivation of tumor suppressor genes with frequencies and characteristics similar to those found in human tumors. For example, mutations in the tumor suppressor genes p53 and INK4a are common, albeit not sufficient, events in the spontaneous immortalization/transformation of normal fibroblasts (1517,4748) and these are precisely the two most frequently inactivated tumor suppressor genes in human cancer, irrespective of tumor type, site and patient age (49,50). Fourth, cultured murine fibroblasts steadily increase their proliferation capacity, reminiscent of tumor progression (51). The process of spontaneous neoplastic progression in vitro has been described in detail by Kraemer et al. (19) and Cram et al. (52). The process can be divided into four stages that correlate with a steady progression in karyotypic instability, including aneuploidy and chromosomal aberrations of marker chromosomes, as occurs in most malignancies. Further, most other indicators of in vitro progression, such as saturation density, a criss-cross and piled up growth pattern, anchorage-independent growth (19), inability to undergo apoptosis (53), alterations in extracellular matrix components (54) and amplification potential (55), correlate with tumorigenicity, i.e. the better cells grow in the Petri dish, the better they also grow in vivo producing tumors in nude mice. Fifth, transformed MEFs and tumors (e.g. 3-methylcholantrene-induced mouse sarcomas) can share common antigens against which lymphoid cells mediate both primary and secondary immune reactions (56) and immunization with transformed MEFs may in some cases protect mice from subsequent challenge with live tumor cells (57).

There are also important specific features that differentiate spontaneous neoplastic transformation in vitro from human tumorigenesis.

Many factors that influence tumorigenesis, such as tissue architecture, blood and lymphatic circulation, cell–cell interactions and a myriad of components (e.g. hormonal) present in the in vivo extracellular milieu, are lost in the Petri dish.

It has been established that cell density influences the rate of spontaneous transformation, i.e. cells transform faster if cultured at high density. An epigenetic origin for this phenomenon has been proposed as an adaptive response of cells to conditions of moderate growth constraint rather than selection among genetically altered cells (58,59), although this view has been challenged (60).

Senescence in cultured mouse cells is not linked to telomere shortening and telomerase activation is not required for transformation, in contrast to what occurs in human tumors (32,33).

In planning transfection experiments a further drawback of MEFs is that these slowly growing primary cells may have low transfection frequencies and the occurrence of crisis may hamper the recovery of a sufficient number of clones.

The above specificities of MEFs undoubtedly represent serious problems in extrapolation of results to the in vivo process of carcinogenesis when factors that prevent or correct the neoplastic phenotype are investigated. Yet, some biases (e.g. those linked to cell density) may be significantly attenuated with appropriate controls. Care should be taken to use MEFs from mouse outbred strains (e.g. CD-1) with no tumor virus (e.g. MuMTV) infection in order to minimize possible influences of inbreeding and virus particles (4). Finally, reagent kits that allow efficient transfection of MEFs have been developed and are commercially available (48).


    Stimulating DNA repair of endogenous damage to delay the onset of spontaneous transformation
 Top
 Abstract
 Introduction
 Spontaneous transformation in...
 How similar are spontaneous...
 Stimulating DNA repair of...
 Rate-limiting steps of BER
 Possible ways to stimulate...
 Concluding remarks
 References
 
An increased efficiency of protective mechanisms may delay the threshold accumulation of cancerous events beyond the average human lifespan. A significant portion of carcinogenic hits in humans is probably of endogenous origin (reviewed in refs 43–46). Endogenous damage is rather frequent and characterized by elevated miscoding properties. For instance, according to recent estimates ~1000 8-oxo-7,8-dihydroguanines (8-oxoG), ~400 uracils and ~9000 abasic (AP) sites are generated daily per human cell (T. Lindahl, quoted in ref. 61). An important repair mechanism dealing with endogenous lesions is BER (62). Development of mouse knockout strains is currently pursued in order to define the role of BER in vivo. Deletion of BER activities leads to various phenotypic consequences, ranging from arrest of embryonic development [such as in the cases of mice deficient in the major AP endonuclease APE/HAP1 (63), DNA polymerase ß (pol ß) (64) or XRCC1 protein (65)] to mild [strains deficient in 3-alkyl-N-purine glycosylase (66,67), poly(ADP) ribose polymerase (68), 8-oxoG DNA glycosylase (OGG1) (69) or uracil-DNA glycosylase (UNG) (70)] or minimal [strains deficient in the endonuclease III homolog NTH1 (71)] effects, thus raising new questions as to the significance and back-up supply of different BER activities. Despite the complexity of this emerging picture, it is most likely that endogenous lesions escaping the `cleaning' activity of BER may contribute to spontaneous mutagenesis/carcinogenesis (4346,61). In particular, some lesions with elevated miscoding properties (8-oxoG and 4,6-diamino-5-formamidopyrimidine) are repaired with low efficiency in human cells (72,73). Recently, achievements have been made in defining the enzymatic reactions that limit the velocity of the whole process. We wonder whether the ability of mammalian cells to repair endogenous lesions may be increased by overexpression of one or more rate-limiting BER activities and whether this may influence the rate of spontaneous transformation of MEFs.


    Rate-limiting steps of BER
 Top
 Abstract
 Introduction
 Spontaneous transformation in...
 How similar are spontaneous...
 Stimulating DNA repair of...
 Rate-limiting steps of BER
 Possible ways to stimulate...
 Concluding remarks
 References
 
BER is a three-armed pathway, depending on the kind of endogenous lesion involved (reviewed in ref.74; Figure 1Go). Some lesions (e.g. uracil) are removed by monofunctional glycosylases (UNG in this case) that only detach the altered base with no incision of the resultant AP site (Figure 1Go, left pathway). Other lesions (e.g. thymine glycol) are removed by bifunctional DNA glycosylases (NTH1) that, in addition to base removal, also incise the resulting AP site by an associated AP lyase activity (Figure 1Go, right pathway). The right-hand pathway is also the main route by which single-strand breaks generated by reactive oxygen intermediates (ROIs) are sealed, a reaction that requires prior removal of a 3'-blocking fragment by a 3'-phosphatase/phosphodiesterase activity (75). Finally, in the case of BER initiated by monofunctional glycosylases (left-hand pathway), resynthesis of a number of repair patches 2–10 nt long is required, dependant on proliferating cell nuclear antigen (PCNA), a phenomenon that occurs in competition with the predominant DNA pol ß-dependent 1 nt insertion pathway (76–78; Figure 1Go, bottom left pathway).



View larger version (43K):
[in this window]
[in a new window]
 
Fig. 1. Outline of the DNA BER pathways in mammals (modified from ref.74 with permission). Altered bases are removed by either monofunctional or bifunctional DNA glycosylases. Monofunctional glycosylases (left-hand pathway) only remove the base, leaving a natural AP site. The latter is 5' incised by the major APE/HAP1 hydrolytic AP endonuclease, which leaves a 5'-terminal dRP residue and a 3'-OH priming terminus. DNA pol ß in most cases inserts 1 nt and the dRP group is removed by its N-terminal dRpase activity. p53 interacts with both APE/HAP1 and pol ß and stabilizes the latter on DNA. The DNA ligase III–XRCC1 complex or DNA ligase I seals the interruption. A number of repair patches are longer (2–10 nt) and require the participation of PCNA (bottom left-hand pathway). Both pol ß and the PCNA-dependent polymerases {delta}/{varepsilon} are involved in the long patch pathway. The 2–10 nt long damaged DNA fragment is displaced during polymerization and removed by DNase IV (FEN1). DNA ligase I is the main sealing activity in the long patch pathway. In the case of bifunctional glycosylases (right-hand pathway) the AP site generated by the glycosylase activity is further 3' incised by an associated AP lyase. The 3' blocking fragment left by AP lyases is trimmed in human cells by the 3' phosphodiesterase activity associated with APE/HAP1 or by the PNK–XRCC1 complex. Synthesis is performed via pol ß only and ligation proceeds as for the short patch pathway initiated by monofunctional glycosylases. The S3 ribosomal protein of Drosophila can remove either a dRP group or a 3'-blocking fragment.

 
Recent work has investigated the rate-limiting steps of BER (reviewed in ref.74). The efficiency of the glycolytic (base removal) step may be important in this regard and depends on the lesion involved. For example, repair of 8-oxoG in mammalian cells is inefficient in comparison with that of other endogenous lesions (72,73) and this is most probably linked to the poor catalytic properties of OGG1 (79,80). Once the base has been removed, BER likely slows down in subsequent trimming steps. It has been shown by Srivastava and co-workers (81) that when BER is initiated by a monofunctional glycosylase (UNG) the rate-determining step is removal of 2-deoxyribose 5-phosphate (dRP) by APE/HAP1 incision (81,82). dRP is predominantly removed in mammalian cells by the 5'-deoxyribophosphodiesterase (dRPase) activity associated with DNA pol ß (8 kDa domain) (83). When BER is initiated by a bifunctional glycosylase (right-hand pathway in Figure 1Go) or when a single-strand break is induced by ROIs the rate-limiting step is most likely removal of 3'-blocking deoxyribose fragments (74,75). 3'-Deoxyribose fragments are predominantly removed in mammalian cells by the 3' repair diesterase activity associated with APE/HAP1 (75,84). The latter protein probably evolved to act preferentially on natural AP sites rather than deoxyribose fragments located at DNA strand breaks (85) and the efficiency of its diesterase activity is low, being ~200-fold lower than the hydrolytic activity (84). A second protein also removes 3'-blocking fragments in eukaryotic cells. The recently characterized human polynucleotide kinase (PNK) is endowed with a phosphatase activity potentially capable of restoring conventional 3'-OH termini to DNA single-strand breaks. This activity is stimulated by XRCC1 protein (86).


    Possible ways to stimulate the BER pathways
 Top
 Abstract
 Introduction
 Spontaneous transformation in...
 How similar are spontaneous...
 Stimulating DNA repair of...
 Rate-limiting steps of BER
 Possible ways to stimulate...
 Concluding remarks
 References
 
Removal of dRP, the rate-limiting step of BER initiated by monofunctional DNA glycosylases (left-hand branch in Figure 1Go), might be accelerated by overexpression of the 8 kDa domain of DNA pol ß (74,82). It has been demonstrated that this domain retains its dRPase functionality when isolated from the rest of the protein (83). The isolated domain efficiently removes 5'-dRP from a pre-incised AP site and its catalytic mechanism as well as a detailed functional analysis of its protein sequence have been determined (87,88). It has recently been shown that expression of the 8 kDa domain effectively protects pol ß-deficient cells from methymethanesulfonate (MMS)-induced cytotoxicity (82). In contrast, expressing the isolated pol ß DNA synthesis activity (Flag-K35A,K68A,K72A pol ß fragment; 82) has no protecting effect and may in fact lead to a genome instability phenotype as overexpression of polymerase results in increased spontaneous mutagenesis and a highly mutagenic tolerance phenotype towards DNA damaging drugs (89,90).

The rate of the right-hand branch of BER in Figure 1Go (initiated by a bifunctional DNA glycosylase) may be increased by overexpression of the major yeast AP endonuclease APN1. Tomicic et al. (91) have shown that Chinese hamster cells become more resistant to DNA damaging agents such as MMS and H2O2 after transfection of the yeast but not the human AP endonuclease gene. Increased resistance to the genotoxicity of oxidizing and alkylating agents after overexpression of APN1 has also been reported by the group of Mark Kelley (92; personal communication). In contrast, expression of human APE/HAP1 has no protective effect in human cells with respect to ROI-generating agents (93,94). These results indicate that expression of yeast (APN1) but not human (APE/HAP1) AP endonuclease protects mammalian cells from certain oxidative and alkylating agents. The different results obtained with the yeast and human enzymes can probably be explained by their different substrate features. As mentioned above, APE/HAP1 shows a very weak 3' repair diesterase activity and probably evolved to incise natural AP sites rather than remove 3'-fragments generated by bifunctional glycosylases or free radical attack (85). The yeast APN1 gene encodes an AP endonuclease function that is homologous to Escherichia coli endonuclease IV and, like the bacterial enzyme, is associated with a robust diesterase activity. The capacity to trim 3'-deoxyribose fragments may thus represent an important protecting factor. The recently discovered 3'-phosphatase activity associated with human PNK might also be investigated for the possibility that its overexpression may stimulate repair of lesions removed by bifunctional glycosylases or ROI-generated single-strand breaks (86).

Finally, the Drosophila ribosomal protein S3 has been reported to be endowed with the capacity to remove both a dRP group from DNA substrates containing 5' incised AP sites and obstructive 3' lesions from DNA substrates containing 3'-incised sites (95). Overexpression of this protein in mammalian cells may thus accelerate both pathways of BER. Further, S3 protein can perform cleavage of 8-oxoG residues, another inefficient step of human BER (96,73). Thus, S3 is a multifunctional repair protein that may act specifically at points of slow-down. Combined overexpression of two proteins (e.g. the 8 kDa pol ß domain with yeast APN1) might be devised in order to achieve acceleration of both pathways of BER (74,97).


    Concluding remarks
 Top
 Abstract
 Introduction
 Spontaneous transformation in...
 How similar are spontaneous...
 Stimulating DNA repair of...
 Rate-limiting steps of BER
 Possible ways to stimulate...
 Concluding remarks
 References
 
By definition, any factor with possible cancer preventing activity has to be investigated in normal cells, in order to determine its protecting efficacy and possible undesirable toxic effects. Normal cells from Li–Fraumeni patients are currently employed to investigate various chemopreventive and antitelomerase agents (28,98,99). While these cells are of the utmost interest, being of human origin and characterized by spontaneous reproducible transformation, they present the drawback of inherent p53 pathology. Rodent fibroblasts in culture may represent an alternative and versatile system for the preliminary evaluation of protective factors. The latter might be investigated on a clonal population that spontaneously evolves from a normal genotypic/phenotypic situation to a malignant one. Thus, the system could be useful to investigators of cancer avoidance mechanisms other than DNA repair. For example, a protective factor that deserves increasing attention is caloric restriction. A number of studies have shown that caloric restriction can modulate endogenous damage and substantially reduce the rate of spontaneous mutagenesis/carcinogenesis (100,101), a phenomenon observable in yeast as in man (102). The underlying mechanisms are currently being investigated in vivo (103), but could also be conveniently studied in the MEF system.

Agents with possible therapeutic properties might also be tested on transformed fibroblasts reverting to a more `normal' phenotype. For example, expression of one or more tumor suppressors can reverse the neoplastic phenotype (104,105), among which p53 is the most promising (106). Super-trans mutants retaining normal transactivating capacity in the presence of dominant negative mutant p53, which inhibits the wild-type protein, have recently been isolated (107). Their tumor suppressing capacity could preliminarily be investigated in the MEF system. Further, it has recently been shown that p53 interacts with and stabilizes DNA pol ß on the damaged substrate, thus markedly improving the efficiency of BER in vitro (108110). Hence, p53 overexpression might have beneficial effects on repair efficiency as well.


    Acknowledgments
 
I thank my colleagues Massimo Bogliolo, Enrico Cappelli and Ottavio Rossi who are trying to translate into facts the theories expressed in this paper. The generous collaboration of Dr Mark R.Kelley (Indiana University, IN) and Dr Robert W.Sobol (NIEHS, Research Triangle Park, NC) is gratefully acknowledged. This work was partially supported by the Italian Association for Cancer Research (AIRC), Telethon, Italy, the National Research Council (grant no. 99.02487.CT04) and the Italian Ministry of Health.


    References
 Top
 Abstract
 Introduction
 Spontaneous transformation in...
 How similar are spontaneous...
 Stimulating DNA repair of...
 Rate-limiting steps of BER
 Possible ways to stimulate...
 Concluding remarks
 References
 

  1. Barrett,J.C. (1993) Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ. Health Perspect., 100, 9–20.[Medline]
  2. Hayflick,L. (1965) The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res., 37, 614–636.
  3. Sanford,K.K. and Evans,V.J. (1982) A quest for the mechanism of `spontaneous' malignant transformation in culture with associated advances in culture technology. J. Natl Cancer Inst., 68, 895–913.[Medline]
  4. DiPaolo,J.A. (1983) Relative difficulties in transforming human and animal cells in vitro. J. Natl Cancer Inst, 70, 3–8.[Medline]
  5. McCormick,J.J. and Maher,V.M. (1988) Towards an understanding of the malignant transformation of diploid human fibroblasts. Mutat. Res., 199, 273–291.[Medline]
  6. McCormick,J.J. and Maher,V.M. (1989) Malignant transformation of mammalian cells in culture, including human cells. Environ. Mol. Mutagen., 14 (suppl. 16), 105–113.[Medline]
  7. Shay,J.W., Wright,W.E. and Werbin,H. (1991) Defining the molecular mechanisms of human cell immortalization. Biochim. Biophys. Acta, 1072, 1–7.[Medline]
  8. Kuroki,T. and Huh,N.-h. (1993) Why are human cells resistant to malignant cell transformation in vitro? Jpn. J. Cancer Res., 84, 1091–1100.[Medline]
  9. Tsutsui,T. and Barrett,J.C. (1997) Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals. Environ. Health Perspect., 105 (suppl. 3), 619–624.[Medline]
  10. Tsutsui,T., Tamura,Y., Suzuki,A., Hirose,Y., Kobayashi,M., Nishimura,H., Metzler,M. and Barrett,J.C. (2000) Mammalian cell transformation and aneuploidy induced by five bisphenols. Int. J. Cancer, 86, 151–154.[Medline]
  11. Todaro,G.J. and Green,H. (1963) Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J. Cell Biol., 17, 299–313.
  12. Röhme,D. (1981) Evidence for a relationship between longevity of mammalian species and life spans of normal fibroblasts in vitro and erythrocytes in vivo. Proc. Natl Acad. Sci. USA, 78, 5009–5013.[Medline]
  13. Kraemer,P.M., Ray,F.A., Brothman,A.R., Bartholdi,M.F. and Cram,L.S. (1986) Spontaneous immortalization rate of cultured Chinese hamster cells. J. Natl Cancer Inst., 76, 703–709.[Medline]
  14. Trott,D.A., Cuthbert,A.P., Overell,R.W., Russo,I. and Newbold,R.F. (1995) Mechanisms involved in the immortalization of mammalian cells by ionizing radiation and chemical carcinogens. Carcinogenesis, 16, 193–204.[Abstract]
  15. Harvey,D.M. and Levine,A.J. (1991) p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts. Genes Dev., 5, 2375–2385.[Abstract]
  16. Harvey,M., Sands,A.T., Weiss,R.S., Hegi,M.E., Wiseman,R.W., Pantazis,P., Giovannella,B.C., Tainsky,M.A., Bradley,A. and Donehower,L.A. (1993) In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene, 8, 2457–2467.[Medline]
  17. Rittling,S.R. and Denhardt,D.T. (1992) p53 mutations in spontaneously immortalized 3T12 but not 3T3 mouse embryo cells. Oncogene, 7, 935–942.[Medline]
  18. Endo,S., Metzler,M. and Hieber,L. (1994) Nonrandom karyotypic changes in a spontaneously immortalized and tumourigenic Syrian hamster embryo cell line. Carcinogenesis, 15, 2387–2390.[Abstract]
  19. Kraemer,P.M., Travis,G.L., Ray,A. and Cram,L.S. (1983) Spontaneous neoplastic evolution of Chinese hamster cells in culture: multistep progression of phenotype. Cancer Res., 43, 4822–4827.[Abstract]
  20. Smith,J.R. and Pereira-Smith,O.M. (1990) Genetic and molecular studies of cellular immortalization. Adv. Cancer Res., 54, 63–77.[Medline]
  21. Azzarone,B. and Pedulla,D. (1976) Spontaneous transformation of human fibroblasts cultures derived from bronchial carcinomata. Eur. J. Cancer, 12, 557–561.[Medline]
  22. Thielmann,H.W., Fischer,E., Dzarlieva,R.T., Komitowski,J., Popanda,J. and Edler,L. (1983) Spontaneous in vitro malignant transformation in a xeroderma pigmentosum fibroblast line. Int. J. Cancer, 31, 687–700.[Medline]
  23. Mukherji,B., MacAlister,T.J., Guha,A., Gillies,C.G., Jeffers,D.C. and Slocum,S.K. (1984) Spontaneous in vitro transformation of human fibroblasts. J. Natl Cancer Inst., 73, 583–593.[Medline]
  24. Boukamp,P., Petrussevska,R.T., Breitkreutz,D., Hornung,J., Markham,A. and Fusenig,N.E. (1988) Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J. Cell Biol., 106, 761–771.[Abstract]
  25. Soule,H.D., Maloney,T.M., Wolman,S.R., Peterson,W.D. Jr., Brenz,R., McGrath,C.M., Russo,J., Pauley,R.J., Jones,R.F. and Brooks,S.C. (1990) Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res., 50, 6075–6086.[Abstract]
  26. Bischoff,F.Z., Yim,S.O, Pathak,S., Grant,G., Siciliano,M., Giovannella,B.C, Strong,L.C. and Tainsky,M.A. (1990) Spontaneous abnormalities in normal fibroblasts from patients with Li-Fraumeni cancer syndrome: aneuploidy and immortalization. Cancer Res., 50, 7979–7984.[Abstract]
  27. Rogan,E.M., Bryan,T.M., Hukku,B., Maclean,K., Chang,A.C.M., Moy,E.L., Englezou,A., Warneford,S.G., Dalla-Pozza,L. and Reddel,R.R. (1995) Alterations in p53 and p16 INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts. Mol. Cell. Biol., 15, 4745–4753.[Abstract]
  28. Shay,J.W., Tomlinson,G., Piatyszek,M.A. and Gollahon,L.S. (1995) Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome. Mol. Cell. Biol., 15, 425–432.[Abstract]
  29. Wright,W.E., Pereira-Smith,O.M. and Shay,J.W. (1989) Reversible cellular senescence: implications for immortalization of normal human diploid fibroblasts. Mol. Cell. Biol., 9, 3088–3092.[Medline]
  30. Sasaki,M., Honda,T., Yamada,H., Wake,N., Barrett,J.C. and Oshimura,M. (1994) Evidence for multiple pathways to cellular senescence. Cancer Res., 54, 6090–6093.[Abstract]
  31. Vojta,P.J. and Barrett,J.C. (1995) Genetic analysis of cellular senescence. Biochim. Biophys. Acta, 1242, 29–41.[Medline]
  32. Wright,W.E. and Shay,J.W. (2000) Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nature Med., 6, 849–851.[Medline]
  33. Artandi,S.E. and DePinho,R.A. (2000) Mice without telomerase: what can they teach us about human cancer? Nature Med., 6, 852–855.[Medline]
  34. Drake,J.W., Charlesworth,B., Charlesworth,D. and Crow,J.F. (1998) Rates of spontaneous mutation. Genetics, 148, 1667–1686.[Abstract/Full Text]
  35. Friedberg,E.C., Walker,G.C. and Siede,W. (1995) DNA Repair and Mutagenesis. ASM Press, Washington, DC, pp. 298–299.
  36. Ames,B.N. (1989) Endogenous oxidative DNA damage, aging and cancer. Free Radic. Res. Commun., 7, 121–128.
  37. Ames,B.N., Shigenaga,M.K. and Hagen,T.M. (1993) Oxidants, antioxidants and the degenerative diseases of aging. Proc. Natl Acad. Sci. USA, 90, 7915–7922.[Abstract]
  38. Sanford,K.K., Parshad,R., Jones,G., Handleman,S., Garrison,C. and Price,F. (1979) Role of photosensitization and oxygen in chromosome stability and `spontaneous' malignant transformation in culture. J. Natl Cancer Inst., 63, 1245–1255.[Medline]
  39. Jones,G.M., Sanford,K.K., Parshad,R., Gantt,R., Price,F.M. and Tarone,R.E. (1985) Influence of added catalase on chromosome stability and neoplatic transformation of mouse cells in culture. Br. J. Cancer, 52, 583–590.[Medline]
  40. Nicotera,T.M., Privalle,C., Wang,T.C., Oshimura,M. and Barrett,J.C. (1994) Differential proliferative responses of Syrian hamster embryo fibroblasts to paraquat-generated superoxide radicals depending on tumor suppressor gene function. Cancer Res., 54, 3884–3888.[Abstract]
  41. Wynder,E.L. and Gori,G.B. (1977) Contribution of the environment to cancer incidence: an epidemiologic exercise. J. Natl Cancer Inst., 58, 825–832.[Medline]
  42. Totter,J.R. (1980) Spontaneous cancer and its possible relationship to oxygen metabolism. Proc. Natl Acad. Sci. USA, 77, 1763–1767.[Medline]
  43. Beckman,K.B. and Ames.,B.N. (1997) Oxidative decay of DNA. J. Biol. Chem., 272, 19633–19636.[Full Text]
  44. Rossman,T.G. and Goncharova,E.I. (1998) Spontaneous mutagenesis in mammalian cells is caused mainly by oxidative events and can be blocked by antioxidants and metallothionein. Mutat. Res., 402, 103–110.[Medline]
  45. Burcham,P.C. (1999) Internal hazards: baseline DNA damage by endogenous products of normal metabolism. Mutat. Res., 443, 11–36.[Medline]
  46. Marnett,L.J. (2000) Oxyradicals and DNA damage. Carcinogenesis, 21, 361–370.[Abstract/Full Text]
  47. Noble,J.R., Rogan,E.M., Neumann,A.A., Maclean,K., Bryan,T.M. and Reddel,R.R. (1996) Association of extended in vitro proliferative potential with loss of p16INK4 expression. Oncogene, 13, 1259–1268.[Medline]
  48. Kamijo,T., Zindy,F., Roussel,M.F., Quelle,D.E., Downing,J.R., Ashmun,R.A., Grosveld,G. and Sherr,C.J. (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell, 91, 649–659.[Medline]
  49. Hall,M. and Peters,G. (1996) Genetic alterations of cyclins, cyclin-dependent kinases and cdk inhibitors in human cancer. Adv. Cancer Res., 68, 67–108.[Medline]
  50. Hainaut,P., Soussi,T., Shomer,B., Hollstein,M., Greenblatt,M., Hovig,E., Harris,C.C. and Montesano,R. (1997) Database of p53 gene somatic mutations in human tumors and cell lines: updated compilation and future prospects. Nucleic Acids Res., 25, 151–157.[Abstract/Full Text]
  51. Barrett,J.C. (1993) Neoplastic progression of Syrian hamster embryo cells in culture. Proc. Soc. Exp. Biol. Med., 202, 30–36.[Medline]
  52. Cram,L.S., Bartholdi,M.F., Ray,F.A., Travis,G.L. and Kraemer,P.M. (1983) Spontaneous neoplatic evolution of Chinese hamster cells in culture: multistep progression of karyotype. Cancer Res., 43, 4828–4837.[Abstract]
  53. Preston,G.A., Lang,J.E., Maronpot,R.R. and Barrett,J.C. (1994) Regulation of apoptosis by low serum in cells of different stages of neoplastic progression: enhanced susceptibility after loss of a senescence gene and decreased susceptibility after loss of a tumor suppressor gene. Cancer Res., 54, 4214–4223.[Abstract]
  54. Freeman,M.R., Song,Y., Carson,D.D., Guthrie,P.D. and Chung,L.W.K. (1991) Extracellular matrix and androgen receptor expression associated with spontaneous transformation of rat prostate fibroblasts. Cancer Res., 51, 1910–1916.[Abstract]
  55. Jonczyk,P., White,A., Lum,K., Barrett,J.C. and Tlsty,D. (1993) Amplification potential in preneoplastic and neoplastic Syrian hamster embryo fibroblasts transformed by various carcinogens. Cancer Res., 53, 3098–3102.[Abstract]
  56. Friend,K., Hellstrom,I. and Hellstrom,K.E. (1976) In vitro sensitization to embryonic antigens. Int. J. Cancer, 18, 843–851.[Medline]
  57. Appleman,L.J., Uyeki,J. and Frey,A.B. (1995) Mouse embryo fibroblasts transformed by activated RAS or dominant-negative p53 express cross-reactive tumor rejection antigens. Int. J. Cancer, 61, 887–894.[Medline]
  58. Yao,A. and Rubin,H. (1992) Sensitivity of transformation to small differences in population density during serial passage of NIH 3T3 cells. Proc. Natl Acad. Sci. USA, 89, 7486–7490.[Abstract]
  59. Rubin,H. (1999) Cell damage, aging and transformation: a multilevel analysis of carcinogenesis. Anticancer Res., 19, 4877–4886.[Medline]
  60. Rittling,S.R. (1996) Clonal nature of spontaneously immortalized 3T3 cells. Exp. Cell Res., 229, 7–13.[Medline]
  61. Kunkel,T.A. (1999) The high cost of living. Trends Genet., 15, 93–94.[Medline]
  62. Lindahl,T. and Wood,R.D. (1999) Quality control by DNA repair. Science, 286, 1897–1905.[Abstract/Full Text]
  63. Xanthoudakis,S., Smeyne,R.J., Wallace,J.D. and Curran,T. (1996) The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice. Proc. Natl Acad. Sci. USA, 93, 8919–8923.[Abstract]
  64. Sobol,R.W., Horton,J.K., Kuhn,R., Gu,H., Singhal,R.K., Prasad,R., Rajewsky,K. and Wilson,S.H. (1996) Requirement of mammalian DNA polymerase ß in base-excision repair. Nature, 379, 183–186.[Medline]
  65. Tebbs,R.S., Flannery,M.L., Meneses,J.J., Hartmann,A., Tucker,J.D., Thompson,L.H., Cleaver,J.E. and Pedersen,R.A. (1999) Requirement for the Xrcc1 DNA base excision repair gene during early mouse development. Dev. Biol., 208, 513–529.[Medline]
  66. Engelward,B.P., Weeda,G., Wyatt,M.D., Broekhof,J.L., de Wit,J., Donker,I., Allan,J.M., Gold,B., Hoeijmakers,J.H. and Samson,L.D. (1997) Base excision repair deficient mice lacking the Aag alkyladenine DNA glycosylase. Proc. Natl Acad. Sci. USA, 94, 13087–13092.[Abstract/Full Text]
  67. Elder,R.H., Jansen,J.G., Weeks,R.J., Willington,M.A., Deans,B., Watson,A.J., Mynett,K.J., Bailey,J.A., Cooper,D.P., Rafferty,J.A., Heeran,M.C., Wijnhoven,S.W., van Zeeland,A.A. and Margison,G.P. (1998) Alkylpurine-DNA-N-glycosylase knockout mice show increased susceptibility to induction of mutations by methylmethane sulfonate. Mol. Cell. Biol., 18, 5828–5837.[Abstract/Full Text]
  68. Menissier-de Murcia,J., Niederganf,C., Trucco,C., Ricoul,M., Dutrillaux,B., Mark,M., Oliver,F.J., Masson,M., Dierich,A., LeMeur,M., Waltzinger,C., Chambon,P. and de Murcia,G. (1997) Requirement of poly(ADP-ribose)polymerase in recovery from DNA damage in mice and in cells. Proc. Natl Acad. Sci. USA, 94, 7303–7307.[Abstract/Full Text]
  69. Klungland,A., Rosewell,I., Hollenbach,S., Larsen,E., Daly,G., Epe,B., Seeberg,E., Lindahl,T. and Barnes,D.E. (1999) Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc. Natl Acad. Sci. USA, 96, 13300–13305.[Abstract/Full Text]
  70. Nilsen,H., Rosewell,I., Robins,P., Skjelbred,C.F., Andersen,S., Slupphaug,G., Daly,G., Krokan,H.E., Lindahl,T. and Barnes,D.E. (2000) Uracil-DNA glycosylase (UNG) deficient mice reveal a primary role of the enzyme during DNA replication. Mol. Cell, 5, 1059–1065.[Medline]
  71. Elder,R.H., Parsons,J.L., Weeks,R.J., Gardiner,L., Margison,G.P., Hendry,J.H. and Hickson,I.D. (2001) Characterization of murine endonuclease III homologue (mNTH1) deficient mice. In Workshop on DNA Repair: Interplay with Other Cellular Processes. Noordwijkerhout, The Netherlands.
  72. Jaruga,P. and Dizdaroglu,M. (1996) Repair of products of oxidative DNA base damage in human cells. Nucleic Acids Res., 24, 1389–1394.[Abstract/Full Text]
  73. Cappelli,E., Degan,P. and Frosina,G. (2000) Comparative repair of the endogenous lesions 8-oxoguanine, uracil and abasic site by mammalian cell extracts: 8-oxoguanine is poorly repaired by human cell extracts. Carcinogenesis, 21, 1135–1141.[Abstract/Full Text]
  74. Frosina,G. (2000) Overexpression of enzymes that repair endogenous damage to DNA. Eur. J. Biochem., 267, 2135–2149.[Abstract/Full Text]
  75. Izumi,T., Hazra,T.K., Boldogh,I., Tomkinson,A.E., Park,M.S., Ikeda,S. and Mitra,S. (2000) Requirement for human AP endonuclease 1 for repair of 3'-blocking damage at DNA single-strand breaks induced by reactive oxygen species. Carcinogenesis, 21, 1329–1334.[Abstract/Full Text]
  76. Matsumoto,Y., Kim,K. and Bogenhagen,D.F. (1994) Proliferating cell nuclear antigen-dependent abasic site repair in Xenopous laevis oocytes: an alternative pathway of base excision DNA repair. Mol. Cell. Biol., 14, 6187–6197.[Abstract]
  77. Frosina,G., Fortini,P., Rossi,O., Carrozzino,F., Raspaglio,G., Cox,L.S., Lane,D.P., Abbondandolo,A. and Dogliotti,E. (1996) Two pathways for base excision repair in mammalian cells. J. Biol. Chem., 271, 9573–9578.[Abstract/Full Text]
  78. Fortini,P., Parlanti,E., Sidorkina,O.M., Laval,J. and Dogliotti,E. (1999) The type of DNA glycosylase determines the base excision repair pathway in mammalian cells. J. Biol. Chem., 274, 15230–15236.[Abstract/Full Text]
  79. Cappelli,E., Hazra,T., Hill,J.W., Slupphaug,G., Bogliolo M. and Frosina,G. (2001) Rates of base excision repair are not solely dependent on levels of initiating enzymes. Carcinogenesis, 22, 387–393.[Abstract/Full Text]
  80. Vidal,A.E., Hickson,I.D., Boiteux,S. and Radicella,J.P. (2001) Mechanism of stimulation of the DNA glycosylase activity of hOGG1 by the major human AP endonuclease: bypass of the AP lyase activity step. Nucleic Acids Res., 29, 1285–1292.[Abstract/Full Text]
  81. Srivastava,D.K., Vande Berg,B.J., Prasad,R., Molina,J.T., Beard,W.A., Tomkinson,A.E. and Wilson,S.H. (1998) Mammalian abasic site base excision repair. Identification of the reaction sequence and rate-determining steps. J. Biol. Chem., 273, 21203–21209.[Abstract/Full Text]
  82. Sobol,R.W., Prasad,R., Evenski,A., Baker,A., Yang,X.-P., Horton,J.K. and Wilson,S.H. (2000) The lyase activity of the DNA repair protein ß-polymerase protects from DNA-damage-induced cytotoxicity. Nature, 405, 807–810.[Medline]
  83. Matsumoto,Y. and Kim,K. (1995) Excision of deoxyribose phosphate residues by DNA polymerase ß during DNA repair. Science, 269, 699–702.[Medline]
  84. Demple,B. and Harrison.,L. (1994) Repair of oxidative damage to DNA: enzymology and biology. Annu. Rev. Biochem., 63, 915–948.[Medline]
  85. Demple,B., Harrison,L., Wilson,D.M., Bennett,R.A., Takagi,T. and Ascione,A.G. (1997) Regulation of eukaryotic abasic endonucleases and their role in genetic stability. Environ. Health Perspect., S4, 931–934.
  86. Whitehouse,C.J., Taylor,R.M., Thistlethwaite,A., Zhang,H., Karimi-Busheri,F., Lasko,D.D., Weinfeld,M. and Caldecott,K.W. (2001) XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell, 104, 107–117.[Medline]
  87. Prasad,R., Beard,W.A., Strauss,P.R. and Wilson,S.H. (1998) Human DNA polymerase beta deoxyribose phosphate lyase. Substrate specificity and catalytic mechanism. J. Biol. Chem., 273, 15263–15270.[Abstract/Full Text]
  88. Prasad,R., Beard,W.A., Chyan,J.Y., Maciejewski,M.W., Mullen,G.P. and Wilson,S.H. (1998) Functional analysis of the amino-terminal 8-kDa domain of DNA polymerase beta as revealed by site-directed mutagenesis. DNA binding and 5'-deoxyribose phosphate lyase activities. J. Biol. Chem., 273, 11121–11126.[Abstract/Full Text]
  89. Canitrot,Y., Frechet,M., Servant,L., Cazayx,C. and Hoffmann,J.S. (1999) Overexpression of DNA polymerase beta: a genomic instability enhancer process. FASEB J., 13, 1107–1111.[Abstract/Full Text]
  90. Canitrot,Y., Lautier,D., Laurent,G., Frechet,M., Ahmed,A., Turhan,A.G., Salles,B., Cazaux,C. and Hoffmann,J.S. (1999) Mutator phenotype of BCR–ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase ß. Oncogene, 18, 2676–2680.[Medline]
  91. Tomicic,M., Eschbach,E. and Kaina,B. (1997) Expression of yeast but not human apurinic/apyrimidinic endonuclease renders Chinese hamster cells more resistant to DNA damaging agents. Mutat. Res., 383, 155–165.[Medline]
  92. Xu,Y., Parsons,S., Hansen,W.K., Williams,D.A. and Kelley,M.R. (1999) Use of DNA base excision repair (BER) genes to protect cells: retroviral expression of the yeast AP endonuclease (APN1) enhances the level of protection of mammalian cells against DNA oxidative and alkylating agents. Env. Mol. Mutagenesis, 33(s30), 69.
  93. Herring,C.J., Deans,B., Elder,R.H., Rafferty,J.A., MacKinnon,J., Barzilay,G., Hickson,I.D., Hendry,J.H. and Margison,G.P. (1999) Expression levels of the DNA repair enzyme HAP1 do not correlate with the radiosensitivities of human or HAP1-transfected rat cell lines. Br. J. Cancer, 80, 940–945.[Medline]
  94. Prieto-Alamo,M.J. and Laval,F. (1999) Overexpression of the human HAP1 protein sensitizes cells to the lethal effect of bioreductive drugs. Carcinogenesis, 20, 415–419.[Abstract/Full Text]
  95. Sandigursky,M., Yacoub,A., Kelley,M.R., Deutsch,W.A. and Franklin,W.A. (1997) The Drosophila ribosomal protein S3 contains a DNA deoxyribophosphodiesterase (dRpase) activity. J. Biol. Chem., 272, 17480–17484.[Abstract/Full Text]
  96. Yacoub,A., Augeri,L., Kelley,M.R., Doetsch,P.W. and Deutsch,W.A. (1996) A Drosophila ribosomal protein contains 8-oxoguanine and abasic site DNA repair activities. EMBO J., 15, 2306–2312.[Abstract]
  97. Limp-Foster,M. and Kelley,M.R. (2000) DNA repair and gene therapy: implications for translational uses. Environ. Mol. Mutagen., 35, 71–81.[Medline]
  98. Herbert,B., Pitts,A.E., Baker,S.I., Hamilton,S.E., Wright,W.E., Shay,J.W. and Corey,D.R. (1999) Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl Acad. Sci. USA, 96, 14276–14281.[Abstract/Full Text]
  99. Herbert,B.S., Wright,A.C., Passons,C.M., Wright,W.E., Ali,I.U., Kopelovich,L. and Shay,J.W. (2001) Effects of chemopreventive and antitelomerase agents on the spontaneous immortalization of breast epithelial cells. J. Natl Cancer Inst., 93, 39–45.[Abstract/Full Text]
  100. Djiuric,Z. and Kritchevsky,D. (1993) Modulation of oxidative DNA damage levels by dietary fat and calories. Mutat. Res., 295, 181–190.[Medline]
  101. Kritchevsky,D. (1999) Caloric restriction and experimental carcinogenesis. Toxicol. Sci., 52 (suppl.), 13–16.[Abstract]
  102. Jiang,J.C., Jaruga,E., Repnevskaya,M.V. and Jazwinski,S.M. (2000) An intervention resembling caloric restriction prolongs life span and retards aging in yeast. FASEB J., 14, 2135–2137.[Full Text]
  103. Kari,F.W., Dunn,S.E., French,J.E. and Barrett,J.C. (1999) Roles for insulin-like growth factor-1 in mediating the anti-carcinogenic effects of caloric restriction. J. Nutr. Health Aging, 3, 92–101.[Medline]
  104. Jin,X., Nguyen,D., Zhang,W.-W., Kyritsis,A.P. and Roth,J.A. (1995) Cell cycle arrest and inhibition of tumor cell proliferation by the p16INK4 gene mediated by an adenovirus vector. Cancer Res., 55, 3250–3253.[Abstract]
  105. Kato,H., Zhou,Y., Asanoma,K., Kondo,H., Yoshikawa,Y., Watanabe,K., Matsuda,T., Wake,N. and Barrett,J.C. (2000) Suppressed tumorigenicity of human endometrial cancer cells by the restored expression of the DCC gene. Br. J. Cancer, 82, 459–466.[Medline]
  106. Yin,Y., Tainsky,M.A., Bischoff,F.Z., Strong,L.C. and Wahl,G.M. (1992) Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell, 70, 937–948.[Medline]
  107. Inga,A., Monti,P., Fronza,G., Darden,T. and Resnick,M.A. (2001) p53 mutants exhibiting enhanced transcriptional activation and altered promoter selectivity are revealed using a sensitive, yeast-based functional assay. Oncogene, in press.
  108. Offer,H., Wolkowicz,R., Matas,D., Blumenstein,S., Livneh,Z. and Rotter,V. (1999) Direct involvement of p53 in the base excision repair pathway of the DNA repair machinery. FEBS Lett., 450, 197–204.[Medline]
  109. Zhou,J. Ahn,J., Wilson,S.H. and Prives,C. (2001) A role for p53 in base excision repair. EMBO J., 20, 914–923.[Abstract/Full Text]
  110. Offer,H., Zurer,I., Banfalvi,G., Reha'k,M., Falcovitz,A., Milyavsky,M. Goldfinger,N. and Rotter,V. (2001) p53 modulates base excision repair activity in a cell cycle-specific manner after genotoxic stress. Cancer Res., 61, 88–96.[Abstract/Full Text]
Received February 19, 2001; revised March 29, 2001; accepted April 11, 2001.





This Article
Abstract
FREE Full Text (PDF)
An erratum has been published
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (8)
Request Permissions
Google Scholar
Articles by Frosina, G.
PubMed
PubMed Citation
Articles by Frosina, G.