Is the Diminuto/Dwarf1 Gene Involved in Physiologic Adrenocortical Size Regulation and Tumor Formation?
Christian A. Koch and
George P. Chrousos
National Institutes of Health
Pediatric and Reproductive Endocrinology Branch
National Institute of Child Health and Human Development
Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: George P. Chrousos, M.D., FACP, FAAP, MACE, National Institutes of Health, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, Building 10, Room 9D42, Bethesda, Maryland 20892. E-mail: chrousog@mail.nih.gov and
kochc{at}exchange.nih.gov
In this issue of JCEM, Sarkar et
al. (1) report very interesting data on the
diminuto/dwarf1 gene in benign cortisol-producing
adrenocortical adenomas. Adrenal nodules are now frequently discovered
by contemporary imaging modalities, with an overall prevalence of about
4% (2, 3). These are in accordance with earlier autopsy
series, which reported adrenal adenomas in up to 8% of cases (4, 5). The majority of these nodules are hormonally inactive, but
when they produce hormones, these are mostly cortisol and/or
aldosterone. The molecular pathogenesis of most adrenocortical adenomas
and carcinomas remains unknown, but the majority of these lesions are
of monoclonal origin (6, 7, 8).
An early and proven approach to elucidate tumorigenesis has been by
analyzing hereditary neoplasms, since these already have an
identifiable "first hit," the inherited gene defect. Indeed,
subsequent hits may be easier identified in familial than in sporadic
tumors (9, 10). Signal transduction systems, including G
protein-coupled receptors and G proteins, when activated
chronically/constitutively in endocrine tissues, may cause an increase
in intracellular levels of cAMP and hormone hypersecretion and/or cell
proliferation. This is the case for at least 40% of somatotropinomas
and toxic thyroid adenomas, in which the GHRH and TSH signaling systems
are pathogenetically involved. However, analysis of components of the
ACTH receptor (ACTHR) signal transduction system in
adrenocortical adenomas or carcinomas has suggested that these are not
involved in a major fashion in the pathogenesis of these tumors
(7, 11, 12), yet aberrant expression of ectopic G-coupled
receptors, such as those of GIP and the catecholamines, have been
determined to be of pathophysiologic significance in some adrenal
adenomas (13). On the other hand, investigations focused
on the involvement of growth factors, such as IGF-II, and components of
apoptotic pathways, such as p53, have yielded useful information about
the pathogenesis of malignant adrenal neoplasms (7, 11, 12, 14).
Further analysis of apoptotic pathways may shed new light on the
pathogenesis of adrenocortical adenomas (15, 16, 17).
Inhibitors of apoptosis (IAP), such as the Bcl-2 family of proteins and
survivin, are conserved evolutionarily and define a "new" category
of "oncogenes," the antiapoptotic genes. Under normal conditions,
IAP may regulate homeostasis between the cytoplasm and key
intracellular organelles. The critical apoptosis-controlling factors
have been defined in the nematode Caenorhabditis elegans,
and one such factor is the product of the diminuto/dwarf1
gene. The sequences of diminuto/dwarf1 homologues are highly
conserved among Caenorhabditis elegans, plants, and mammals.
The genomic sequence of Diminuto spans approximately 37,000
bp encoded by nine exons. The diminuto/dwarf1 protein is 561
amino acids long with a calculated molecular mass of 65 kDa (18, 19). In Arabidopsis plants, diminuto is
important in regulating cell elongation (18). Mutant
diminuto genes lead to reduced expression of a ß-tubulin
gene, TUB1, resulting in smaller plant cells and shorter
plants (dwarfs). Plants use campesterol as a precursor for
brassinosteroid biosynthesis. Diminuto/dwarf1 is located on
the cytoplasmic side of microsomal membranes and is important for the
conversion of isofucosterol to sitosterol and of
24-methylenecholesterol to campesterol (18) (Fig. 1
). Interestingly, ß-sitosterol
from pumpkin seed extracts has been successfully used to treat benign
prostatic hyperplasia in men (20), suggesting that this
plant steroid might lead to reduced expression of
diminuto/dwarf1 in the prostate gland and subsequent cell
shrinkage.
Recently, the human diminuto homologue termed "selective
Alzheimers disease indicator 1" (seladin-1) was shown to
confer resistance to Alzheimers disease-associated neurodegeneration
and oxidative stress (19). Seladin-1 is
ubiquitously expressed in human tissues. In brains obtained from
nondemented subjects, transcripts of seladin-1 were detected
in all areas tested with highest levels in the hippocampus and
amygdala. In brains of Alzheimers patients, seladin-1
expression was reduced in the inferior temporal lobe, amygdala, and
hippocampus, compared with neurons in the frontal cortex from the same
patients and to those of frontal and temporal cortices from control
nondemented brains. Seladin-1 exerts antiapoptotic effects
by inhibiting caspase 3 activation. Also, because it contains a domain
characteristic for oxidoreductases, it may be required for flavin
adenine dinucleotide-dependent oxidation of a specific metabolic
intermediate necessary for cell growth and differentiation. Memory
loss, hippocampal, and brain cortical atrophy are well recognized
complications of long-term glucocorticoid excess (21, 22, 23, 24)
and might be related to reduced expression of an "antiapoptotic"
diminuto type protein.
In peripheral human tissues, high diminuto transcript levels
are found in the adrenal gland, prostate, lung, fetal liver and other
tissues and organs (19). It is, therefore, not surprising
that Sarkar et al. (1) found
diminuto expression throughout the adrenal cortex zones,
with the highest transcript levels in the zona fasciculata.
Whether cortisol production by these adrenocortical adenomas was caused
by diminuto and/or ACTHR overexpression remains unknown. The
latter was suggested by a study showing persistent expression of ACTHR
in adenomatous tissue, implicating a role in the autonomous production
of cortisol via intracellular cAMP elevations (11). Lack
of ACTH, a trophic factor for the adrenal cortex, leads to increased
apoptosis and adrenal atrophy. Indeed, a decrease of ACTH secretion by
the CRH antagonist antalarmin leads to marked increases in
adrenocortical apoptosis and diminution of adrenal size, mostly as a
result of zona fasciculata atrophy, whereas stress has the
opposite effect (i.e. a marked decrease in adrenocortical
apoptosis and adrenal hypertrophy/hyperplasia) (16). How
crucial diminuto expression is in the physiologic regulation
of adrenal size is unknown but testable (Fig. 2
). On the other hand, because of the
antiapoptotic properties of seladin-1, diminuto
overexpression in adrenocortical adenomas may participate in their
pathogenesis, as a result of the increased growth of the clones that
overexpress it (1).

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Figure 2. Diminuto expression and the
hypothalamic-pituitary-adrenal axis. In a patient with a
cortisol-producing adrenal adenoma, the adrenal cortex adjacent to the
adenoma and the contralateral adrenal cortex show reduced
diminuto expression, increased apoptosis and atrophy,
whereas the adenoma itself has increased diminuto
expression and diminished apoptosis. Increased cortisol levels in this
patient cause reduced CRH and ACTH secretion, and might lead to reduced
diminuto expression and increased apoptosis in the
hypothalamic and hippocampal brain regions with subsequent atrophy in
these areas. In a patient with normal functioning adrenal glands,
diminuto expression and apoptosis are regulated by
physiological needs and exposure to different radicals and toxins, with
variable cortisol production rates.
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Although it remains to be determined whether diminuto
overexpression in adrenocortical adenomas plays a role in tumor
formation, other IAP such as survivin and bcl-2
have been shown to serve as prognostic markers in other endocrine
tumors. For instance, overexpression of survivin and/or
bcl-2 is a highly significant independent risk factor for
disease progression in neuroblastomas (25, 26). However,
such overexpression might be related to gene amplification by genomic
instability (27): in neuroblastoma, there is gain of 17q25
containing the survivin locus. In adrenocortical neoplasms,
previous studies only examined selected chromosomal regions for genetic
aberrations (7). It remains unknown whether amplification
of 1p32 containing the diminuto locus occurs in
adrenocortical adenomas, possibly explaining the overexpression of
diminuto in these tumors, another testable hypothesis.
Footnotes
Abbreviations: ACTHR, ACTH receptor; IAP, inhibitors of
apoptosis; seladin-1, selective Alzheimers disease
indicator 1.
Received September 13, 2001.
Accepted September 13, 2001.
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