Evolution of the coordinate regulation of glycolytic enzyme genes by hypoxia
Department of Molecular and Cellular Pharmacology, University of Miami Medical Center, Miami, FL 33136, USA e-mail: kwebster{at}chroma.med.miami.edu
Accepted 27 May 2003
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Summary |
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Key words: hypoxia, anaerobic, glycolysis, gene expression, HIF-1, evolution
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Introduction |
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Oxygen regulation of glycolysis
Fig. 1A shows the glycolytic
pathway, where 12 enzymes catalyze the anaerobic fermentation of glycogen to
lactic acid, generating 3 moles of ATP per glucosyl unit. The process is an
order of magnitude less efficient than oxidative metabolism, where 32 moles of
ATP are generated per 2 or 3 moles of glucose, depending on whether glucose or
glycogen is the substrate. The scheme shows the input and output points of the
pathway. There are numerous molecular modulators of glycolytic flux, the most
famous of which was discovered in 1860 by Louis Pasteur
(Pasteur, 1861). Pasteur
showed that oxygen inhibits fermentation and that glucose consumption is
inversely proportional to the oxygen availability, i.e. that the glycolytic
pathway is positively regulated by hypoxia. Pasteur received wide recognition
for this stunning observation that became universally known as the `Pasteur
Effect'. In 1987, our laboratory reported the observations shown in
Fig. 1B (Webster, 1987
). We theorized
that since oxygen is a potent and ancient regulator of glycolytic flux, it
might also be a regulator of glycolytic enzyme gene expression. We isolated
and cloned rodent cDNAs for six glycolytic enzymes (indicated with asterisks
on Fig. 1A), and we used these
to measure transcription rates of the genes in muscle cells exposed to
hypoxia. Fig. 1B shows a
composite of the transcription of six glycolytic enzyme cDNAs compared with
that of mitochondrial cytochrome c. Chronic hypoxia caused a
significant and coordinated activation of transcription of these genes.
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Conservation of glycolytic enzyme genes
The 12 mammalian glycolytic enzyme genes are genetically unlinked and
dispersed around the genome, mostly on different chromosomes
(Webster and Murphy, 1988).
These are some of the most ancient and highly conserved proteins and genes
known, with strong conservation of both the peptide and DNA sequences even
between higher mammals and bacteria
(Lonberg and Gilbert, 1985
;
Peak et al., 1994
;
Poorman et al., 1984
).
Fig. 2 shows a Southern blot
illustrating the remarkable conservation of pyruvate kinase (PK) and lactate
dehydrogenase (LDH) with strong cross-homology of DNA fragments between yeast
and human DNA. Glycolytic enzymes were probably among the very first enzyme
pathways to appear, allowing primitive organisms to utilize simple
carbohydrates as energy stores and to release energy by coupling the breakdown
to high-energy phosphates
(Fothergill-Gilmore and Michels,
1993
; Romano and Conway,
1996
). Although structural and functional aspects of glycolytic
enzyme genes and proteins have been strongly conserved, it is not clear how
gene regulatory mechanisms evolved or how the pathway established a coordinate
response of widely dispersed genes to oxygen tension.
Fig. 2 also illustrates a
second intriguing feature of glycolytic enzyme genes, namely an apparently
selective accumulation of pseudogenes in rodents, particularly mouse and rat.
This is reflected in the dramatic increase of the number of hybridizing bands
in these species, and was first described by Piechaczyk for the GAPDH gene
(Piechaczyk et al., 1984
). Our
results demonstrate increased numbers of pseudogenes of PK and LDH
(Fig. 2), as well as GAPDH,
aldolase, triosephosphate isomerase, phosphoglycerate kinase and enolase (not
shown), and suggest that the effect may be common to the entire pathway of
genes. We do not know why or how this occurred.
|
Precambrian: bacterial glycolytic genes
The chart in Fig. 3 shows
sections of time dating back to when life first appeared on earth. This early
period is known as the Precambrian and it is divided into Hadean, Archean,
Paleoproterozoic, Mesoproterozoic and Neoproterozoic. The oldest fossils
include bacteria and other microorganisms that date to about 3.8 billion years
ago (BYA). Glycolytic enzymes are evident in the Archean period, 2 BY before
the earliest oxygen-requiring species and almost 4 BY before the present
pathways (Gebbia et al., 1997;
Kelly and Adams, 1994
;
Peak et al., 1994
).
Qualitative trends in the amount of global biomass are projected in
Fig. 3B. Acquisition of
methanogenesis by Archaebacteria probably supported an early expansion of life
forms (DeLong et al., 1994
;
Koch, 1998
;
O'Callaghan and Conrad, 1992
;
Papagiannis, 1984
;
Reeve, 1992
), and biomass
probably increased significantly before the dip and subsequent massive
expansion of the Cambrian period. Natural selection working on the expanding
biomass produced increasingly high levels of biological sophistication and
diversity within the anaerobic kingdoms. In fact, molecular studies of extant
bacterial species such as the Archaebacteria and thermophyllic sulfur bacteria
indicate complex patterns of gene expression under anoxia, including the
regulation of bioenergetic gene expression by elemental sulfur and phosphorus
(Brunner et al., 1998
;
Fardeau et al., 1996
;
Friedrich, 1998
;
Janssen and Morgan, 1992
;
Kelly and Adams, 1994
;
Ma et al., 1995
;
Segerer et al., 1985
). There
is an intriguing parallel between sulfur regulation of bioenergetic pathways
in the Archean era microorganisms and oxygen regulation in eukaryotes. Oxygen
replaced sulfur as the terminal electron acceptor of carbohydrate catabolism,
and may simultaneously have parasitized some molecular features of the
regulation over billions of years. Numerous aspects of the Archaebacteria and
bacterial gene regulatory mechanisms have been conserved and elaborated in
higher animals while others, including the bacterial operon, have been largely
replaced. The rearrangement of primitive prokaryotic glycolytic enzyme gene
operons into unlinked genes on eukaryotic chromosomes requires the parallel
segregation, multiplication and/or insertion of regulatory elements with
trans-acting protein factors to allow the coordinated function of the
pathway (Alefounder and Perham,
1989
; Barnell et al.,
1990
; Gebbia et al.,
1997
).
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The Archean period is characterized by what would be an extremely toxic
atmosphere for current life forms, with methane, nitrogen and ammonia as the
major components (Kasting,
1993; Papagiannis,
1984
). Fig. 4A
illustrates an Archean coastline 3.5 BYA. The mounds in the foreground are
stromatolites, multiple layers of calcified microbial colonies, mostly
bacteria and fungi, dating back almost to the beginning of life
(Papagiannis, 1984
;
Reid et al., 2000
). These
structures form the best record of Archean and the early Proterozoic period,
known as the third domain of life (Koch,
1998
). Stromatolite fields can still be found in parts of South
African and Western Australia. They were common throughout the Precambrian
periods until about 1.0 BYA, when herbivorous predators probably featured
significantly in their decline. Fig.
4B shows a piece of stroma fossil from the Bitter Springs
formation of central Australia, dated at 0.85 BYA. These fossils are known as
carbon films, dark compressions in the rock revealing the outlines of ancient
species in the forms of spheres, circles, ribbons and leaf-like structures.
The diversity represents more than 2 BY of anaerobic evolution generating
complex phyla of obligate microbial anaerobes, including Archaebacteria,
cyanobacteria and possibly unicellular flagellates. Studies on present day
descendants of these microorganisms, in particular the obligate anaerobic
hyperthermophilic Archaea, indicate that they have complex systems of
bioenergetic pathways (Fardeau et al.,
1996
; Janssen and Morgan,
1992
; Kelly and Adams,
1994
; Ma et al.,
1995
). Thermoproteus tenax is an obligate anaerobic
hyperthermophile and a descendent of one of the earliest Archea dating back to
3-4 BYA.
|
The first glycolytic enzymes in the Archean period probably contributed
mainly anabolic, gluconeogenic functions
(Conway, 1992;
Romano and Conway, 1996
;
Selig et al., 1997
), with
catabolic functions being acquired subsequently as kinases appeared to use
ATP, ADP or pyrophosphate as phosphate shuttles
(Romano and Conway, 1996
).
There are some unique characteristics of Archean era glycolysis; for example
catalysis of reactions by the enzymes glucokinase and phosphofructokinase
(PFK) in T. tenax is dependent on ADP and pyrophosphate as cofactors.
This allows these key steps to be functionally reversible, permitting
gluconeogenesis as well as glycolysis, a feature not possible in the later
bacterial and eukaryotic pathways
(Mertens, 1991
;
Siebers et al., 1998
;
van der Oost et al., 1998
).
There is evidence for both divergent and convergent evolution of glycolytic
genes, but not divergence from a single multifunctional glycolytic protein or
gene cluster (Barnell et al.,
1990
; Fothergill-Gilmore,
1986
; Fothergill-Gilmore and
Michels, 1993
; Rossman,
1981
). Sequence and crystallographic data favor the divergent
evolution of for example monophosphoglycerate mutase and diphosphoglycerate
mutase, and possibly glyceraldehyde-3-P dehydrogenase and phosphoglycerate
kinase from respective common ancestors, but convergence appears to have
played a greater role in the development of all of the other 11 enzymes
(Fothergill-Gilmore, 1986
;
Fothergill-Gilmore and Watson,
1989
). For example, there is no evidence of a common ancestor for
any of the four glycolytic kinases or of the seven enzymes that bind
nucleotides, with the exception of those mentioned above. Rather, it seems
likely that the pathway resulted from the chance assembly of independently
evolving enzymes and genes, probably in association with the co-evolution of
other functions and linked pathways.
Substrate regulation by operons in bacteria
Many functionally related bacterial genes are organized into physical
operons that are regulated by a master operator element, usually positioned at
the 5' end of the operon, which regulates the transcriptional rate of
all genes in the operon (Alefounder and
Perham, 1989; Barnell et al.,
1990
; Hannaert et al.,
2000
; Liaud et al.,
2000
; Unkles et al.,
1997
). Evidence for glycolytic enzyme gene operons include linked
pyruvate kinase and PFK genes in Clostridium acetobutylicum
(Belouski et al., 1998
);
clustered genes for phosphoglycerate kinase (PGK), triosephosphate isomerase
(TPI), phosphoglycerate mutase and enolase in Baccilus subtilis
(Leyva-Vazquez and Setlow,
1994
); linkage of GAPDH, PGK and TPI in Borrelia megaterium,
Borrelia bungorferi and Borrelia hermsii
(Gebbia et al., 1997
;
Schlapfer and Zuber, 1992
);
clustering of fructose 1,6-biphosphate aldolase, 3-phosphoglycerate kinase and
GAPDH in E. coli (Alefounder and
Perham 1989
), and clustering of the glucose-6 dehydrogenase,
6-phosphogluconate dehydratase and glucokinase genes with a putative glucose
transporter in Zymomonas mobilis
(Barnell et al., 1990
). These
glycolytic enzyme gene operons may be regulated independently of each other or
globally. In the latter condition the multiple operons behave as a unit,
termed a modulon, which is coordinately regulated by one or more
wide-ranging master regulatory proteins. The best example of modulon
regulation is through the cAMP receptor protein (CRP) or catabolite gene
activator protein (CAP), which can activate or repress numerous regulons in
response to substrate availability (Bledig
et al., 1996
; Kumari et al.,
2000
; Luesink et al.,
1998
; Tobisch et al.,
1999
). Because substrate fluctuation was the principal selection
pressure for evolving Archean microorganisms, modulons became the principal
mechanism for the coordinated regulation of all genes involved in carbohydrate
metabolism, including glycolytic enzymes. However even in early Moneras there
is evidence for fine tuning in the form of functional segregation and
preferential targeting of specific genes, in particular those destined to
become the `key regulatory enzymes'. For example, in E. coli an
operon containing phosphofructokinase, pyruvate kinase and
L-lactate dehydrogenase, all `key enzymes', is selectively
regulated through a 5' cAMP response element that binds the positive
factor CcpA. Levels of CcpA in turn are determined by substrate availability
(glucose, galactose, fructose) (Luesink et
al., 1998
; Tobisch et al.,
1999
). The grouping of PFK and PK is clearly significant because
the operon components tend to favor contiguous functions within the glycolytic
pathway.
Oxygen regulation in prokaryotes
Oxygen exerted massive selection pressures on prokaryotes and engineered
cooperativity between energy storing and releasing pathways, including
substrate-level phosphorylation and electron transport by dedicated carriers
including cytochromes. The oxygen-regulated switching in bacteria (and
possibly archaebacteria; Chistoserdova et
al., 1988; Iwasaki et al.,
1995
; Segerer et al.,
1985
) includes the activation and/or repression of key enzyme
genes and operons involved in oxidative metabolism and glycolysis. This
includes positive and negative factors regulated by oxygen tension or redox
potential and involves contributions from at least three major regulatory
pathways. These include the Arc and FNR systems, which regulate gene
expression pre-transcriptionally in response to the redox state of the
environment, and the CsrA-CsrB system, which differentially regulates the
expression of glycogen synthesis, gluconeogenesis and glycolytic genes by
conditionally regulating RNA stability. The latter regulation has been
recently reviewed and will not be discussed here
(Bunn and Poyton, 1996
); we
will briefly consider the oxygen-regulated Arc and FNR systems because they
may be the precursors of eukaryotic glycolytic enzyme gene regulation by
hypoxia.
The Arc system is involved in the repression of aerobic functions under
anaerobic conditions. Arc A represses the expression of the succinate
dehydrogenase, citric acid cycle and glyoxylate cycle enzyme genes, and
activates cytochrome d oxidase under hypoxic conditions, thereby
shutting off the succinate dehydrogenase-cytochrome oxidase pathway and
activating electron transport through the d-cytochrome, which has a
higher affinity for oxygen (Parkinson and
Kofoid, 1992). The mechanism is a classical two-component
signal-transducing system, involving a membrane-bound redox sensor and protein
kinase (ArcB) and a cytoplasmic regulator (ArcA) with a DNA-binding domain
(see Fig. 5). Signals from the
electron transport chain (probably the redox state of heme or other
iron-containing component) activate ArcB, which transmits the signal to ArcA
and initiates the cascade of gene regulation. The FNR system is also involved
in the anaerobic activation and repression of a wide variety of metabolic
enzymes by a mechanism that parallels that of the CAP system
(Chang and Meyerowitz, 1994
;
Parkinson and Kofoid, 1992
).
Expression of more than ten enzymes involved in anaerobic energy metabolism,
including fumarate reductase and glycerol-3-phosphate dehydrogenase, is
induced when the FNR system is activated
(Spiro and Guest, 1991
).
Activation is believed to involve a redox switch within the FNR protein
involving cysteine-bound metal ions. A conformational change of the protein
creates an active DNA binding site that promotes transcription. The target
sequence for activated FNR usually resides about 40 bp upstream of the
transcriptional initiation site and includes the consensus sequence
nTTGATnnnnATCAAn, which is a typical binding site for dimer-DNA-binding
proteins containing helix-turn-helix motifs
(Kiley and Reznikoff, 1991
).
This is significant because it may be the first example of a positive-acting
transcription factor with helix-turn-helix motifs that is activated by hypoxia
and involved in the coordinate regulation of genes that ultimately determine
glycolytic functions. Conformational regulation by reversible binding of
metals to cysteine sites is reminiscent of the redox responses of zinc finger
transcription regulators, the most common regulators of gene expression in
eukaryotes (Webster et al.,
2001
). Redox-dependent conformational changes also contribute to
the transcriptional activation of mammalian glycolytic enzyme genes by
specific helix-turn-helix factors (see below).
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Notably, none of the aerobic/anaerobic regulatory systems described above
directly regulate glycolytic enzyme genes, although cross talk between the
Arc, FNR and CcpA networks causes changes in the transcription rates of
glycolytic enzyme operons in response to carbohydrate. The absence of a direct
regulation of glycolytic enzyme gene transcription (by substrates, alternative
pathways such as sulfur, or oxygen) in the Archean era and subsequently in
bacteria would be predicted if such regulation was acquired during the
selection and gene shuffling that accompanied the transition to oxidative
metabolism. The establishment of direct oxygen regulation of glycolytic enzyme
genes may in fact have paralleled mitochondrial symbiosis and the
establishment of compartmented energy pathways. Photosynthetic cyanobacteria
underwent a major expansion 1.5 BYA, producing >1000 different variants and
initiating a rapid increase of atmospheric oxygen
(Kasting, 1993;
Reid et al., 2000
).
Atmospheric oxygen during the Archean period was less than 1% of the current
level, but by about 1.8 BYA it was 15%, and probably increased to the current
level by 0.5 BYA. This accumulated oxygen had a major impact on life. It has
been estimated that as much as 99% of the existing anaerobic life forms were
extinguished by the toxic byproducts of reactive oxygen (Cannio, 2000). Oxygen
allowed the rapid diversification and expansion of survivors because of the
increased energy made available from oxidative metabolism. The main expansion
occurred within the eukaryotic kingdom, stimulated by the high
energy-producing potential of mitochondria. Mitochondria contributed a highly
efficient energy production system that was partially insulated from other
cellular functions. Metabolic and gene regulatory pathways, including
responses to hypoxia, arose in parallel to coordinate mitochondrial and
glycolytic function (Webster et al.,
1990
).
Eukaryotic glycolytic genes
The archeological period known as the `Vendian' is thought to include the
earliest species that survived the oxygen explosion
(Li et al., 1998;
Rasmussen et al., 2002
;
Seilacher et al., 1998
).
Organisms within this period bridge the gap between the late Precambrian and
early Cambrian periods and represent the ancestors of most if not all
eukaryotes. Rich deposits of Vendian fossils have been discovered in three
major locations: the Ediacara Hills in Southeast Australia, the Russian Winter
coast, and Misty Point in Newfoundland, Canada. Examples of these fossils are
shown in Fig. 6. Vendian life
forms representing the transition to eukaryotic organisms include sponges,
hydra, filamentous algae and fungi. Estimates of the start of the Vendian
period vary from about 0.8 to more than 1 BYA. Yeasts belong to the Fungi, and
are all facultative anaerobes capable of growth with or without functional
mitochondria (Ferguson and von Borstel.,
1992
).
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Studies with the yeast Saccharomyces cerevisae illustrate
elegantly the powerful selection pressures that are inherent for a dual
aerobic/anaerobic lifestyle. The requirement to survive and grow under
different oxygen tensions has promoted the establishment of a system for
coordinately and simultaneously regulating multiple unlinked genes
(Zitomer et al., 1997). To
grow anaerobically, S. cerevisae requires supplements of sugar,
unsaturated fatty acids, sterol and methionine because of oxygen-dependent
steps in the biosynthesis of these essential metabolites. Under hypoxic
conditions the genes encoding these oxygen-dependent enzymes are coordinately
induced so that optimal use can be made of oxygen as it becomes the limiting
substrate (Jiang, Y. et al.,
2001
; Vasconcelles et al.,
2001
). At least 10 genes are induced when S. cerevisae
are cultured under hypoxia and there are close parallels between these
regulatory pathways and those that regulate glycolytic enzyme and other
hypoxia-responsive genes in higher mammals. The S. cerevisae OLE1
gene encodes a
9 fatty acid desaturase that is essential for fatty acid
synthesis. OLE1 is induced by hypoxia, transition metals and iron chelators.
An element in the OLE1 gene promoter with the sequence ACTCAACAA is
responsible for the response to hypoxia. This element named LORE (for low
oxygen responsive element) can confer hypoxia inducibility to a heterologous
promoter and binds a specific hypoxia-inducible protein. Additional LORE
elements have been identified in the promoters of other hypoxia-inducible
genes, suggesting a mechanism for a global synchronized response to hypoxia in
S. cerevisae (see Fig.
7). This is perhaps the earliest evidence of a regulatory system
capable of mediating a global response of multiple unlinked genes to changes
in oxygen tension. Although the sequence of the LORE does not resemble any
identified mammalian LORE (or hypoxia-response element, HRE), the common
responses of S. cerevisae LOREs and eukaryotic HREs to hypoxia,
transition metals and iron chelators suggests related pathways (see below;
Jiang, Y. et al., 2001
;
Vasconcelles et al.,
2001
).
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Neither the LORE nor ROX elements appear to directly regulate glycolytic
enzyme genes. This implies that the regulation of these genes by hypoxia was a
later acquisition, possibly associated with multicellularity and genome
expansion. Glycolytic enzyme genes in S. cerevisae are, however,
strictly regulated by the carbon source through a mechanism that may be the
forerunner of oxygen regulation. The rates of transcription of different
glycolytic enzyme genes increases by up to 100-fold when S. cerevisae
is switched from acetate to fermentative growth on glucose. The regulation
involves complex interactions between a number of cis-acting promoter
elements and trans-acting transcription factors that include GCR1,
RAP1, ABF1 and GAL11 proteins (Bunn and
Poyton, 1996). There is evidence that genes encoding the key
glycolytic control enzymes PK and PFK are preferentially regulated (for a
review, see Nishi et al.,
1995
). The regulation of glycolytic enzymes and genes by
carbohydrate metabolism in yeast is a powerful illustration of the importance
of bioenergetic pathway switching in determining the fitness of an organism.
Under anaerobic fermentative conditions glycolytic enzyme proteins can account
for >50% of the total yeast protein
(Nishi et al., 1995
). This
level of protein production would be a selective disadvantage for oxidative
growth and in fact it is not seen in any other eukaryote. Aerobic adaptation
and multicellularity during the Cambrian expansion involved a systematic
reduction in the maximum expression levels of glycolytic genes through a
decrease of basal promoter strength. Genome expansion for glycolytic enzyme
genes also included the acquisition of multiple tissue-specific isoforms as
separate genes and the acquisition of mechanisms to simultaneously and
coordinately regulate the entire pathway of genes in response to oxygen
tension.
Glycolytic genes in multicellular eukaryotes
Multicellular eukaryotes of increasing complexity developed during the
Vendian period and expanded rapidly in the Devonian, Carboniferous, and
Permian periods. The Rhynie valley in Scotland is one of the richest sources
of Devonian deposits (Fig. 8)
with extensive fossil evidence of higher plants dating back 0.8 billion years.
Like fungi, higher plant glycolytic enzyme genes have introns, TATA control
elements and transcriptional regulatory sites; unlike earlier eukaryotes and
prokaryotes, all of the glycolytic enzyme genes are physically separated and
scattered seemingly randomly around the genome, mostly on separate
chromosomes, posing additional mechanistic requirements for coordinate
regulation (Webster and Murphy,
1988).
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Analyses of the root system of the monocotyledon Zea mays (maize)
lead to the first identification of hypoxia-responsive DNA elements in
glycolytic enzyme gene promoters. The root systems of many higher plants
penetrate deeply into anaerobic waterlogged earth and cells, particularly at
the root tips, have adapted to anoxia. Exposure of maize root cells to hypoxia
results in the induction of approximately 20 proteins, deemed anaerobic
polypeptides (Dennis et al.,
1988; Dolferus et al.,
1994
; Olive et al.,
1991
). Many of these proteins are enzymes involved in glycolytic
or fermentative carbohydrate metabolism and include two alcohol
dehydrogenases, glucose phosphate isomerase, aldolase and lactate
dehydrogenase. Two anaerobic response elements (ARE) were identified in the
proximal promoters of the aldolase and Adh1 genes. The first
site contained the consensus sequence TGGTTT and was present in the
aldolase promoter at -70 bp upstream from the transcription start
site, and in the Adh1 promoter at position-111. The second site
contained the consensus GC(G/C)CC and was present at -135 and -120 of the
Adh1 promoter (Olive et al.,
1991
). Mutation of these elements resulted in the loss of response
to hypoxia. Further studies revealed the specific binding of a protein to the
GC-rich element and this protein was designated GCBP-1 (GC-rich binding
protein-1). This protein has not been fully characterized; its abundance is
not changed by hypoxia, it requires accessory proteins and/or
post-translational modifications to mediate transcriptional activation by
hypoxia, and its binding to the GC site is competed by members of the Sp1
family of zinc finger transcription factors. There may be strong parallels
between this regulatory pathway and that described below for the regulation of
mammalian muscle-specific pyruvate kinase (PKM) and ß-enolase genes
(Discher et al., 1998
;
Webster et al., 2001
). These
elements represent the earliest examples of hypoxia response elements directly
controlling individual glycolytic enzyme genes. They may also provide a clue
as to how hypoxia response elements were selected from other stress response
pathways of regulation, including temperature and osmolarity, both of which
featured significantly as evolutionary selection pressures.
Hypoxia, dehydration and hypothermia induce the Adh gene in the
roots of the dicotyledon, Arabidopsis thaliana. The promoter contains
a single GT/GC motif, which has a similar sequence to the monocotyledon
Zea mays GC site described above, except that the GT motif is in
reverse orientation (Dolferus et al.,
1994). However, the Arabidopsis Adh promoter contains a
second motif with the sequence CCACGTGC. The core sequence of this motif,
ACGTG, is the binding site for the major hypoxia regulatory binding protein in
mammalian cells called hypoxia inducible factor-1
(HIF-1
).
Interestingly this motif appears to be required for Adh gene
induction by hypothermia, dehydration and UV light, but not hypoxia, whereas
the hypoxia response is determined by the GT/GC sequence. The reversal of the
use of these elements in mammalian genes seems remarkable, although as
discussed below, both HIF-1 and GC elements may contribute to the hypoxia
response of glycolytic enzyme genes in mammals.
Regulation of glycolytic enzyme genes in fish, insects and
mammals
The regulation of glycolytic enzyme genes by hypoxia in insects, fish,
reptiles, birds and mammals and possibly all mobile multicellular species is
multifactorial, with clear origins in the prokaryotic and fungal regulatory
systems (Bacon et al., 1998;
Bruick and McKnight, 2001
;
Hochachka and Lutz, 2001
;
Jiang, H. et al., 2001
;
Soitamo et al., 2001
). Animal
glycolytic enzyme genes are regulated both coordinately and individually by
hypoxia-responsive transcription factors including hypoxiainducible
factor-1
(HIF-1
), SP-1 family factors, AP-1 and possibly metal
response elements (MREs) (Discher et al.,
1998
; Hochachka and Lutz,
2001
; Murphy et al.,
1999
; Webster et al.,
2000
). HIF-1
is probably the main component and is largely
responsible for coordinating the induction. The core consensus sequence for
HIF-1
binding is ACGT, and active HIF-1
binding sites have been
reported in at least eight glycolytic enzyme genes, usually in the proximal
promoter regions (Riddle et al.,
2000
). Glycolytic enzyme genes with HIF-1 sites include PFK,
aldolase, pyruvate kinase, PGK, enolase, LDH, hexokinase and GAPDH
(Firth et al., 1994
;
Semenza et al., 1996
). Active
HIF-1 binding sites are present in these genes at the following positions:
mouse PFKL, first intron, +336/+361; human PGK1, promoter, -309/-290, and
5' untranslated region, +31/+11; human ENO1, promoter, -585/-610; human
ALDA, promoter, -204/-180, and first intron, +125/+150; mouse LDHA, promoter,
-75/-50. Although other regulatory elements may be involved, the HIF-1 pathway
appears to be sufficient to account for the observed induction of these genes
by hypoxia. It is not yet clear whether HIF-1 contributes to the regulation of
the other glycolytic enzyme genes, glycogen phosphorylase, phosphoglucomutase,
phosphoglucose isomerase or triosephosphate isomerase. Glycogen phosphorylase
is induced by hypoxia in tissues from turtles to humans
(Mehrani and Storey, 1995
;
Parolin et al., 2000
) and our
laboratory has show that TPI is induced coordinately by hypoxia with the other
glycolytic enzymes in cultured muscle cells
(Webster, 1987
). It seems
probable that the full complement of glycolytic enzyme genes is induced at
some level by hypoxia.
The HIF-1 pathway has been described in insects and fish but not in plants or fungi, and it is possible that the pathway developed in the Silurian period about 500 MYA when highly mobile sea and land species were evolving. The sequence ACGTC is essential (although not sufficient) for gene activation by HIF-1 and, as discussed above, the same sequence is required for the hypothermia, dehydration and the UV response of Arabidopsis genes involved in carbohydrate metabolism. It seems likely that this recognition sequence and the protein that binds it are related in plants and animals, and this may provide the link between gene regulation in hypoxic root tips and the HIF-1 pathway of insects, fish, birds and mammals.
Role of HIF-1
Fig. 9 shows the essential
features of gene regulation by HIF-1. The pathway allows for a rapidly
reversible activation of genes in response to hypoxia because the HIF-1
gene is constitutively active and regulation is at the level of protein
stability. Under aerobic conditions HIF-1
is targeted by the ubiquitin
degradation system through a redox modulated hydroxyproline residue, which
appears to regulate the conformation of the protein
(Bruick and McKnight, 2001
;
Jaakkola et al., 2001
). This
results in rapid degradation such that HIF-1
protein is undetectable in
most aerobic cells and tissues but accumulates within minutes when the cells
are exposed to hypoxia. The development of a rapid and coordinated response to
changes of oxygen tension may have been a significant force in the early
Cambrian period, providing a selective advantage to cells and organisms that
could tolerate aerobic and hypoxic environments and shuttle rapidly between
the two. Our experiments show that switching of muscle cells from aerobic to
hypoxic growth conditions results in an approximately 12-fold increase of
glucose consumption (and lactic acid production) and net 3- to 5-fold increase
of glycolytic enzyme proteins (Webster et al.,
1993
,
1994
,
1999
). To maintain
equilibrium, glucose transport and acid efflux must be correspondingly
increased. The glucose transporter GLUT-1 is also positively regulated through
HIF-1
, introducing an elegant coordination of glucose utilization and
uptake. Hypoxia-regulation of proton translocation genes has not been reported
but seems likely. The coordination of glycolytic enzyme activity with glucose
and acid regulation may have been an early Silurian adaptation that paralleled
multicellularity and increased mobility.
HIF-1 appears to be the only transcription factor that is dedicated
specifically to the regulation of gene expression by hypoxia. However, it is
not the only factor involved in the response. It may be significant that the
`TGGTTT' and G/C elements that mediate the response of Arabidopsis to
hypoxia resemble the binding sites for the transcription factors activator
protein-1 (Ap-1; TGATTC) and the Sp-1 family (GGGCCC), both of which
contribute to the regulation of glycolytic enzyme genes by hypoxia. The Ap-1
proteins, c-Fos and c-Jun, are induced by hypoxia in neuronal cells, cancer
cells and cardiac myocytes (Webster et
al., 1993), and Ap-1 binding has been shown to be required for the
induction of tyrosine hydroxylase as well as the endothelin-1 gene by
HIF-1
(Hu et al., 1998
;
Millhorn et al., 1997
;
Yamashita, 2001
). Both factors
are present in most glycolytic enzyme gene promoters, often in multiple
copies. Sp1 has an important role in the regulation of the muscle-specific
glycolytic enzyme genes encoding pyruvate kinase (PKM) and ß-enolase
(Discher et al., 1998
). The
gene promoters of the latter genes do not have consensus HIF-1
binding
sites but they are induced by hypoxia
(Discher et al., 1998
).
Regulation in this case appears to correlate with the differential binding of
Sp1 and Sp3 to common sites (Fig.
9). The differential regulation of Sp1 and Sp3 has been shown to
regulate other GC-dependent promoters by interacting with multiple classes of
related factors (Birnbaum et al.,
1995
; Hagen et al.,
1994
; Kumar and Butler,
1997
; Luca et al.,
1996
; Majello et al.,
1997
). Therefore Ap-1 and Sp1 can operate in concert or separately
with HIF-1
to fine-tune and coordinate the responses of glycolytic
enzyme genes to hypoxia in higher animals and humans.
![]() |
Summary and Conclusions |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
The ability to modulate glycolytic enzyme gene expression in response to
oxygen tension probably conveyed significant selective advantages to life
forms at many stages of evolution. The advantages of such a switch are evident
from the waterlogged root tips of plants to hibernating mammals, exercising
`glycolytic' skeletal muscles in all higher animals, and ischemic skeletal and
cardiac muscles in humans (Hochachka and
Lutz, 2001; Mehrani and
Storey, 1995
; McClelland, et
al., 1998
; Vogt et al., 2002;
Webster et al., 2000
). Hypoxia
is a much more frequent condition than is generally realized. The HIF-1
pathway is activated at oxygen tensions less than about 40 mmHg (5%
O2) (Iyer et al.,
1998
; Semenza,
2001
). Whereas the PO in the atmosphere is
about 150 mmHg, the normal PO of most tissues is in the
range 50-70 mmHg (Hochachka,
1999
). Therefore small changes in the supply and demand for oxygen
can tilt the balance to promote the activation of hypoxia-dependent genes.
Both cardiac and skeletal muscles can survive extended periods of hypoxia,
during which time glycolytic enzyme genes become fully induced
(Webster and Murphy, 1988
;
Webster et al., 1990
). When
maximally activated, the levels of glycolytic enzymes in muscle can reach
almost 20% of total soluble protein
(Webster, 1987
;
Webster and Murphy, 1988
).
Continuous production of this level of protein may be of negative selective
value under aerobic conditions when oxidative phosphorylation produces more
than 95% of cellular ATP, but it may be essential for the survival of cells
and tissues subjected to chronic or repetitive hypoxia.
![]() |
Dedication |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Acknowledgments |
---|
![]() |
References |
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