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UR 238 - Unité de Nutrition Cellulaire et Moléculaire, INRA de Theix, 63122 Saint Genès Champanelle, France
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • amino acid • CHOP • asparagine synthetase • gene expression • human cultured cells
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Because
important dispensable AA stores do not exist as they do for lipids or
glucose, AA metabolism can be altered in response to various forms of
malnutrition or trauma (e.g., sepsis, fevers or thermal burns). A
dramatic diminution of the plasma concentration of certain AA occurs
after a dietary imbalance, a deficiency of any one of the essential AA
or a deficient intake of protein. Moreover, multicellular organisms are
unable to synthesize all of the AA; as a result, they have to adjust
several of their physiologic functions involved in the adaptation to AA
limitation by regulating numerous genes. For example, an AA limitation,
as occurs in animals subjected to a low protein diet, increases the
level of insulin-like growth factor binding protein-1 (IGFBP-1)
mRNA, thereby participating in the down-regulation of growth
(Jousse et al. 1998
). Other genes have been shown to be
regulated by AA availability. Marten et al. (1994)
showed that the abundance of several different mRNAs [e.g., C/EBP
homologous protein (CHOP), C/EBPß or ubiquitin] is affected by AA
deprivation. The regulation of asparagine synthetase (AS) and CHOP
expression by AA availability has been studied at the molecular level
(Bruhat et al. 1997
, Guerrini et al. 1993
). AS is the gene encoding the enzyme responsible for the
biosynthesis of asparagine from aspartate and glutamate. CHOP encodes a
transcription factor that regulates certain aspects of the response of
cellular stress. CHOP induction is generally linked to a perturbation
of the endoplasmic reticulum (ER) unfolded protein response (UPR).
However, it was shown recently that AA deprivation induces CHOP
expression through a pathway distinct from the ER stress-signaling
cascade (Jousse et al. 1999b
).
The mechanisms involved in the AA control of gene expression are poorly
understood in mammalian cells. However, both transcription and
translation can be regulated by AA availability. It has been shown that
the induction of CHOP and AS genes by AA deprivation involves
transcriptional mechanisms. A promoter fragment, when linked to a
reporter gene, is sufficient to reproduce the regulation of CHOP or AS
expression by leucine deprivation in cultured cells (Bruhat et al. 1997
, Guerrini et al. 1993
). Moreover, it
has been shown that AA availability can regulate mRNA translation. AA
(particularly leucine) can modulate the protein synthesis rate through
changes in the phosphorylation of translation factors and regulatory
proteins such as eucaryotic initiation factor 2
(eIF-2),
eucaryotic initiation factor 4E (eIF4E) and protein S6 (Hara et al. 1998
, Kimball et al. 1999
, Wang et al. 1998
, Xu et al. 1998
).
In yeast, the regulation of gene transcription in response to AA
deprivation has been studied extensively. Two types of regulation have
been characterized: 1) a specific control whereby numerous
operons are regulated by the specific AA end products of the
corresponding enzymes (Marczak and Brandriss, 1991
,
Sze et al., 1992
); and 2) a general control
process whereby a subset of genes is coordinately induced by depriving
the cell of any single AA (Hinnebusch, 1988
). In the
general control process, uncharged tRNAs accumulate under conditions of
deprivation, thus stimulating the activity of the protein kinase GCN2,
which turns on a signaling pathway leading to the translational
up-regulation of GCN4. GCN4 is the transcription factor that is
responsible for the pleiotropic increase in gene expression. Regulation
of genes involved in AA metabolism can contain elements of both general
and specific controls.
In this study, experiments were conducted to understand the signaling pathways that link AA limitation to regulated gene expression in mammalian cells. In particular, we examined whether one or several control process are activated in response to AA availability and the role of protein synthesis inhibition due to AA limitation in the induction of gene expression.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Human cervical carcinoma cells (HeLa) and human hepatoma cells (HepG2) cells were cultured at 37°C under 95% air/5% CO2 in Dulbecco’s modified Eagle’s medium (DMEM)/F12 (Sigma Chemical, St. Louis, MO), containing10% decomplemented fetal bovine serum and 10% fetal bovine serum, respectively.
When indicated, DMEM/F12 lacking leucine, methionine, glutamine or lysine was used. For phenylalanine, histidine, tryptophan, asparagine, arginine, cysteine, alanine or several nonessential AA (NEAA; aspartate + glutamate + glycine + proline + serine) deprivation experiments, MEM medium (Life Technologies, Frederick, MD) was used. For AA deprivation experiments, 10% dialysed calf serum was used. The amino acid content was measured at the end of the experiments and was found not to change during the incubation time. Cycloheximide (CHX) was purchased from Sigma Chemical.
RNA isolation and Northern blot analysis.
Total RNA was prepared as described previously (Chomczynski and Sacchi 1987
). Northern blots were performed according to the
procedure of Sambrook et al. (1989)
; then RNA was
cross-linked to the membrane by UV irradiation. The human CHOP cDNA
(BH1), generously provided by Dr. N. J. Holbrook (Park et al. 1992
) was used as a probe. BH1 plasmid was linearized by
Pst1, and 32P-riboprobes were synthesized
(Sambrook et al. 1989
) using T7 RNA polymerase (Promega,
Madison, WI). Prehybridization was carried out for 2 h at 55°C
in 50% formamide, 6X SSC, 5X Denhardt’s reagent, 0.5% SDS and 10
mg/L yeast tRNA. Hybridization was carried out for 16 h at 55°C.
The membranes were washed for 15 min at 55°C successively in 2X SSC
containing 0.1% SDS, 0.5X SSC containing 0.1% SDS and 0.1X SSC
containing 0.1% SDS. The human AS cDNA, generously provided by Dr.
Basilico (Gong et al. 1991
), was used as a probe. The
gel-purified HindIII fragment was labeled by random
priming with 32P dCTP [Ready-To-Go-DNA Labeling Beads
(-dCTP) by Amersham Pharmacia Biotech, Uppsala, Sweden].
Prehybridization was carried out for 2 h at 42°C in 50%
formamide, 6X SSC, 5X Denhardt’s reagent and 0.5% SDS. Hybridization
was carried out for 16 h at 42°C. The membranes were washed for
15 min. at 42°C successively in 2X SSC containing 0.1% SDS and 0.5X
SSC containing 0.1% SDS. Labeled bands were visualized and quantified
using a PhosphorImager and the IMAGEQUANT software (Molecular
Dynamics). To control for variation in either the amount of RNA in
different samples or loading errors, all blots were rehybridized with a
DNA probe corresponding to 18S RNA.
Protein synthesis measurements.
HeLa cells were incubated in the indicated medium. During the last three hours of incubation, L-35S-methionine (Amersham) was added. The medium was then removed and the cells were incubated for 30 min in cold 0.3 mol/L trichloroacetic acid. The wells were washed once with trichloroacetic acid and three times with water. The radioactivity incorporation into trichloroacetic acid–precipitable material was measured by liquid scintillation counting after protein solubilization in 0.1 mol/L NaOH plus 0.5% SDS.
Plasmids used for transfection experiments.
The plasmid pCHOP-luciferase (LUC) corresponds to the human CHOP
promoter region from nucleotides -649 to + 91 fused to the LUC gene in
the pGL3 plasmid (Promega). The plasmid pAS-LUC corresponds to the
human AS promoter region fused to the LUC gene in the pGL3 plasmid. The
AS promoter fragment was kindly given by Dr. Basilico (New York
University, New York, NY) and corresponded to the construct p3.4CAT
published by Gong et al. (1991)
.
DNA transfection and LUC assay.
HeLa cells were plated in 12-well dishes and transfected by the calcium
phosphate coprecipitation method as described previously (Davis et al. 1986
). LUC plasmid (2 µg) was
transfected into the cells along with 0.1 µg
pCMV-ß-galactosidase (ß-Gal), a plasmid carrying the bacterial
ß-Gal gene fused to the human cytomegalovirus immediate-early
enhancer/promoter region, as an internal control. Cells were exposed to
the precipitate for 16 h, washed twice in PBS and then incubated
with DMEM/F12 containing 10% calf serum. Twenty-four hours after
transfection, cells were starved for 16 h. After starvation, cells
were harvested in 150 µL of lysis buffer (Promega) and
centrifuged at 13,000 x g for 2 min. The
supernatant (20 µL) was assayed for LUC activity
(PRODEMAT, Anduze, France). ß-Gal activity was measured as described
by Hall et al. (1983)
. Relative LUC activity was given
as the ratio of relative light unit/relative ß-gal unit. All values
are the means calculated from the results of at least three independent
experiments.
Statistical analysis.
Data were analyzed by t test (Excel, Microsoft, Seattle, WA). Differences were considered significant when P < 0.05. Values presented are means ± SEM
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Among the AA-regulated genes, only the regulation of AS and CHOP
has been studied at the molecular level. To understand the signaling
pathway activated by AA limitation and leading to gene regulation, we
studied the regulation of CHOP and AS expression in response to
deprivation of an individual AA. The expression of CHOP and AS genes
varied according to the AA that was omitted from the culture medium
(Fig. 1
). Among the AA tested, 16 h of deprivation in alanine or NEAA
(aspartate, glutamate, glycine, proline, serine) did not affect CHOP
and AS expression. On the other hand, deprivation of leucine,
methionine, lysine, phenylalanine or tryptophan induced the expression
of both CHOP and AS genes in the two cell lines tested. A discrepancy
between CHOP and AS expression was observed in response to deprivation
of histidine, asparagine, cysteine and methionine. AS expression was
induced in response to deprivation of histidine, asparagine or
cysteine, whereas CHOP expression was little affected. On the contrary,
methionine deprivation induced CHOP mRNA content to a greater extent
than did AS mRNA. Similar regulation of CHOP and AS genes was observed
in HeLa and HepG2 cells, suggesting that the same regulatory mechanisms
are involved in both cellline.
|
). The transcriptional activity of the AS promoter fragment was induced
in response to leucine, methionine, cysteine, asparagine or histidine
deprivation. The activity of the CHOP promoter fragment was poorly
increased by cysteine, asparagine or histidine limitation, whereas it
was strongly induced in response to methionine deprivation. Taken
together, these results show that CHOP and AS genes are regulated
differentially, according to the AA that is omitted from the culture
medium.
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Deprivation of an individual AA can lead to protein synthesis inhibition and therefore induce cellular stress. In this set of experiments, we investigated the possible link between protein synthesis inhibition and CHOP and AS expression.
Deprivation of essential AA plus cysteine inhibited
L-35S-methionine incorporation and
induces CHOP and AS expression, whereas a limitation in alanine and
NEAA did not effect either protein synthesis rate or gene expression
(Fig. 3A
). Asparagine deprivation induced AS expression (Fig. 1)
and did not
affect L-35S-methionine incorporation
into the cells (Fig. 3)
.
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). However, a moderate
limitation in leucine (30 µmol/L) did not reduce global
protein synthesis, whereas CHOP and AS mRNA levels were increased
significantly. Therefore, a moderate AA restriction, which does not
inhibit protein synthesis, can induce CHOP and AS expression.
Because a slight inhibition of protein synthesis, which is not
detectable using methionine incorporation, could be responsible for
gene induction, we inhibited methionine incorporation by treatment of
the cells with CHX, a protein synthesis inhibitor. As shown in
Figure 4A
, CHX strongly inhibited methionine incorporation into cell proteins. A
CHX concentration (0.2 mg/L) inhibiting ~50% of
L-35S-methionine incorporation into
cell proteins did not induce CHOP or AS expression. Taken together,
these results show that there is no association between CHOP and AS
expression and protein synthesis inhibition due to AA limitation.
Therefore, protein synthesis inhibition is not a prerequisite for gene
induction in response to AA deprivation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Nevertheless, the knowledge of the molecular mechanisms
involved in the AA regulation of mammalian gene expression are limited.
In particular, the signaling pathways mediating the AA response are not
known. The objective this paper was to gain a better understanding of
the signaling pathways involved in the AA control of genes expression.
We investigated whether one or several pathway(s) are involved in gene
regulation by AA limitation and whether a cellular stress due to
protein synthesis inhibition subsequent to AA limitation is responsible
for gene regulation.
Because no general accumulation of mRNAs in AA-deprived cells has
been observed (Marten et al. 1994
), cells must have a
specific mechanism(s) that enables them to alter one specific pattern
of gene expression in response to AA deprivation. In a previous study
(Jousse et al. 1999b
), we showed that a limitation in
one AA does not activate the UPR and therefore regulates CHOP
expression through a pathway that is distinct from the ER stress
signaling cascade. Consequently, the pathways linking the AA limitation
to gene regulation remain unknown. However, in mammalians cells,
several of the following observations suggest that depletion in any one
AA activates a signaling pathway that could be related to the general
control of yeast: 1) CHOP and AS mRNAs are regulated by the
level of many different AA (Bruhat et al., 1997
,
Hutson and Kilberg, 1994
, Thissen et al., 1994
). 2) Andrulis et al. (1979)
showed a correlation among asparagine starvation, amino-acylation
of tRNAasn and AS activity. 3)
Inhibition of the leucyl-tRNA synthetase induces CHOP expression
(Jousse et al. 1999b
).
In addition, we hypothesize that different pathways will be activated,
depending on the AA that is omitted from the culture medium. Our
results effectively demonstrate that, in addition to this type of
general control, starvation in certain AA can activate other pathway(s)
that lead to up-regulation of a distinct pattern of genes. This
conclusion can be drawn from the study of the regulation of AS and CHOP
expression in response to methionine, histidine, asparagine or cysteine
depletion. CHOP expression was strongly induced in response to
methionine deprivation but was affected only slightly by histidine,
asparagine or cysteine deprivation. Under the same experimental
condition, AS expression was induced equally in response to a
limitation in any one of these AA. The discrep-ancy between
AS and CHOP regulation by individual AA limitation can be explained by
the existence of at least two mechanisms involved in the regulation of
gene expression by AA limitation (Fig. 5
). Depletion in any one of these AA can activate a signaling pathway
that could be related to the general control process described in
yeast. This mechanism will lead to the up-regulation of several
genes, including AS and CHOP. In addition, methionine deprivation can
also turn on a more specific control process that activates CHOP
expression. Both the general and specific control processes could
regulate certain target genes such as CHOP. Similar examples have been
found in yeast. LEU4, which encodes the first enzyme of the pathway of
leucine biosynthesis, is subject to regulation by the following:
1) the general control system in response to starvation in
any AA and 2) the Leu3p transcriptional activator in
response to the levels of the metabolic intermediate -isopropyl
malate, which serves as a sensor of leucine availability (Friden and Schimmel 1988
).
|
, Guerrini et al. 1993
). The transcriptional activity of the CHOP promoter
fragment is strongly induced in response to methionine deprivation,
whereas it is only slightly affected by cysteine, asparagine or
histidine deprivation. The activity of the AS promoter is increased by
a limitation in any one of the AA tested. These results show that, like
mRNA content, transcription of the CHOP and AS genes is regulated by
different mechanisms according to the AA that is omitted from the
culture medium. However, we cannot exclude the possibility that
post-transcriptional events are involved in the regulation of the
mRNA content of the endogenous gene. Indeed, in response to histidine
deprivation, AS mRNA content was strongly enhanced, whereas the
transcriptional activity of the AS promoter fragment was only slightly
affected. This result also could be explained by the lack of regulatory
elements in the AS promoter fragment. The main effect of AA limitation on cellular functions is the inhibition of protein synthesis. Several lines of evidence show that CHOP or AS induction is dissociated from the inhibition of the protein synthesis. First, a low leucine concentration can induce CHOP and AS expression but does not significantly inhibit total protein synthesis. Second, deprivation of asparagine induces AS expression but has a limited effect on L-35S-methionine incorporation into the cell proteins. Third, CHX treatment, reproducing protein synthesis inhibition resulting from leucine deprivation, does not induce CHOP or AS expression. Taken together, these results show that although a limitation in AA affects L-35S-methionine incorporation, protein synthesis inhibition by itself is not responsible for CHOP and AS induction. However, we cannot exclude the possibility that AA limitation activates a mechanism involved in both protein synthesis inhibition and induction of gene expression. For example, free transfer RNAs could accumulate in response to AA deprivation and rapidly induce the up-regulation of CHOP or AS expression. The accumulation of free tRNA and the lack of charged tRNA could also inhibit protein synthesis.
In humans, amino acids requirements have been very well studied
(Millward 1994
, Rose 1957
, Young 1998
). In healthy adult humans, nine amino acids (valine,
isoleucine, leucine, lysine, methionine, phenylalanine, threonine,
tryptophan and histidine) were shown to be indispensable. Therefore,
these amino acids must be supplied in the diet. Amino acid and protein
homeostasis are finely maintained by the integrated action of all of
the tissues and organs. However, in certain situations, nitrogen
metabolism can become deranged, and a loss of body protein and/or amino
acids will be at the expense of essential elements. The main factors
affecting nitrogen metabolism and aminoacidemia are nutritional status
and various forms of stress. For example, amino acid patterns have been
shown to be altered in humans and animals when there is a deficient
intake of protein, a dietary imbalance of amino acids or a deficiency
in any one of the essential amino acids. Moreover, in response to
various forms of stress, changes in the patterns of free amino acids
are observed in plasma and urine. It follows that mammals must adjust
several of their physiologic functions involved in the
defense/adaptation to amino acid limitation by regulating the
expression of numerous genes.
The idea that amino acids can regulate gene expression has just begun
to emerge. It is now clear that amino acids by themselves can play (in
concert with hormones) an important role in the control of gene
expression; however, the underlying processes have only begun to be
discovered. Among the genes regulated by amino acid availability, AS
encode a gene responsible for the biosynthesis of one amino acid
(asparagine), and CHOP encode a transcription factor. The physiologic
importance of CHOP regulation in response to amino acid limitation is
not yet understood. However, through its association with the C/EBP
transcription factor, CHOP could be involved in the regulation of
several mechanisms (McKnight et al. 1989
) involved in
the response to nutrient limitation. Further work will be required to
understand the molecular steps by which the cellular concentration of
an individual AA can regulate gene expression. These studies will
provide an understanding of the role of AA in the regulation of
cellular functions such as cell division, protein synthesis or
proteolysis. The molecular basis for gene regulation by dietary protein
intake is important in the regulation of physiologic functions of
individuals living under conditions of restricted or excessive food
intake.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AA, amino acid; AS, asparagine synthetase; ß-Gal, ß-galactosidase; CHOP, C/EBP homologous protein; CHX, cycloheximide; DMEM, Dulbecco’s modified Eagle’s medium; eIF-2, eucaryotic initiation factor 2; eIF4E, eucaryotic initiation factor 4E; ER, endoplasmic reticulum; IGFBP-1, insulin-like growth factor binding protein-1; LUC, luciferase; UPR, unfolded protein response.
Manuscript received October 28, 1999. Initial review completed November 29, 1999. Revision accepted January 31, 2000.
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A. Bruhat, J. Averous, V. Carraro, C. Zhong, A. M. Reimold, M. S. Kilberg, and P. Fafournoux Differences in the Molecular Mechanisms Involved in the Transcriptional Activation of the CHOP and Asparagine Synthetase Genes in Response to Amino Acid Deprivation or Activation of the Unfolded Protein Response J. Biol. Chem., December 6, 2002; 277(50): 48107 - 48114. [Abstract] [Full Text] [PDF]
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F. Siu, P. J. Bain, R. LeBlanc-Chaffin, H. Chen, and M. S. Kilberg ATF4 Is a Mediator of the Nutrient-sensing Response Pathway That Activates the Human Asparagine Synthetase Gene J. Biol. Chem., June 28, 2002; 277(27): 24120 - 24127. [Abstract] [Full Text] [PDF]
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P. C. Rodriguez, A. H. Zea, K. S. Culotta, J. Zabaleta, J. B. Ochoa, and A. C. Ochoa Regulation of T Cell Receptor CD3zeta Chain Expression by L-Arginine J. Biol. Chem., June 7, 2002; 277(24): 21123 - 21129. [Abstract] [Full Text] [PDF]
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F. Siu, C. Chen, C. Zhong, and M. S. Kilberg CCAAT/Enhancer-binding Protein-beta Is a Mediator of the Nutrient-sensing Response Pathway That Activates the Human Asparagine Synthetase Gene J. Biol. Chem., December 14, 2001; 276(51): 48100 - 48107. [Abstract] [Full Text] [PDF]
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 T. Matsukawa, Y. Inoue, Y. Oishi, H. Kato, and T. Noguchi Up-Regulation of Upstream Stimulatory Factors by Protein Malnutrition and Its Possible Role in Regulation of the IGF-Binding Protein-1 Gene Endocrinology, November 1, 2001; 142(11): 4643 - 4651. [Abstract] [Full Text] [PDF]
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 R. Franchi-Gazzola, R. Visigalli, V. Dall'Asta, R. Sala, S. K. Woo, H. M. Kwon, G. C. Gazzola, and O. Bussolati Amino acid depletion activates TonEBP and sodium-coupled inositol transport Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1465 - C1474. [Abstract] [Full Text] [PDF]
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