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Molecular and Cellular Biology, May 2000, p. 3616-3625, Vol. 20, No. 10
Forschungszentrum Karlsruhe, Institute of
Toxicology and Genetics,1 and University
of Karlsruhe, Institute of Genetics,3 76021 Karlsruhe, Germany, and Laboratoire de Génétique de
la Radiosensibilité, Département de Radiobiologie et de
Radiopathologie, Direction des Sciences du Vivant, Commissariat a
l'Energie Atomique, CEFAR, 92265 Fontenay-aux-Roses,
France2
Received 20 August 1999/Returned for modification 18 October
1999/Accepted 28 February 2000
Irradiation of cells with short-wavelength ultraviolet light (UVC)
changes the program of gene expression, in part within less than 15 min. As one of the immediate-early genes in response to UV, expression
of the oncogene c-fos is upregulated. This immediate induction is regulated at the transcriptional level and is transient in
character, due to the autocatalyzed shutoff of transcription and the
rapid turnover of c-fos mRNA. In an experiment analyzing the kinetics of c-fos mRNA expression in murine fibroblasts
irradiated with UVC, we found that, in addition to the initial
transient induction, c-fos mRNA accumulated in a second
wave starting at 4 to 5 h after irradiation, reaching a maximum at
8 h, and persisting for several more hours. It was accompanied by
an increase in Fos protein synthesis. The second peak of
c-fos RNA was caused by an UV dose-dependent increase in
mRNA half-life from about 10 to 60 min. With similar kinetics, the
mRNAs of other UV target genes (i.e., the Kin17 gene,
c-jun, I Men and mice and derived cells in
culture react to irradiation with ultraviolet light A, B, or C (UVA,
-B, or -C) by initiating a new program of gene expression that has been
named the UV response (reviewed in references 24,
30-32, and 66). Most of the response known so far is transcriptional, as shown by run-on analyses or promoter studies. Within 10 min, the immediate-early genes
c-fos, c-jun, and junB are
transcriptionally activated, preceded by activation of transcription
factors such as SRF-TCF, ATF-2, and CREB (15, 33, 55).
NF- Other levels of gene regulation have, as yet, received less attention.
Stabilization of protein is responsible for the UV-DNA lesion-induced
increases in p53 and E2F-1 levels (10, 11, 45, 71). Nothing
is known about UV influences on pre-RNA splicing and almost nothing
about the regulation of mRNA turnover. The turnover of UV-induced
c-fos transcripts at its peak level is rapid, and several
structural features of c-fos RNA have been made responsible
for this rapid degradation (12, 36, 37, 50, 56, 63). One of
the features common to rapid-turnover transcripts, sequences in the 3'
untranslated region (UTR) (reviewed in reference
16), are eliminated in Fos-expressing retroviruses (19, 20, 51). These viral fos transcripts are
stable, enhancing oncogenicity.
The mammalian UV response resembles in part the bacterial SOS response
(reviewed in references 31 and
69). One of the key proteins in the SOS response is
the bacterial RecA protein. Eukaryotic proteins with similarities to
the bacterial RecA protein have been identified. Most of them are
encoded by rad genes which are induced in response to
irradiation and involved in the repair of irradiation-induced DNA
lesions (7, 62). By screening a murine expression library
with anti-RecA antibodies, the nuclear protein Kin17 was identified
(2, 3). Kin17 and RecA appear to share an epitope located in
the RecA carboxy-terminal region that is involved in the regulation of
DNA binding and in the SOS response in Escherichia coli,
while differing in most other respects (38, 39, 43, 68).
Overexpression of Kin17 seems to be toxic for mammalian cells
(40). Bacterially produced Kin17 binds to DNA (64,
65). The physiologic function of Kin17 is unknown as yet.
We report here that UVC treatment of several mammalian cell lines
produces two peaks of c-fos RNA abundance, at 30 to 60 min and at about 8 h. While the first peak represents the known
transcriptional response, this newly discovered second peak of
accumulation is, as we report here, due to UV-induced stabilization of
c-fos RNA. Several other short-lived RNAs are also
stabilized. The UV-induced accumulation of Kin17 RNA is exclusively
caused by RNA stabilization and follows the kinetics and
characteristics of the second c-fos peak. Other inducers of
c-fos, such as phorbol ester or growth factors, cannot
trigger the biphasic c-fos response and cannot reduce RNA
turnover. Furthermore, RNA stabilization is induced in cells defective
in the Xeroderma pigmentosum group A (XPA) DNA repair gene
xpa at a lower UV dose than in wild-type cells. Although
this is reminiscent of the induction of p53, UV-induced elevation of
p53 protein levels is not an intermediate in the stabilization of
c-fos and Kin17 RNA.
Cell lines and their treatment.
The following cell lines
were used: NIH 3T3 cells were obtained from Peter Gruss,
Göttingen, Germany; p53
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
UV-Induced Stabilization of c-fos and
Other Short-Lived mRNAs
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
B, and c-myc) were stabilized (e.g.,
Kin17 RNA from 80 min to more than 8 h). The delayed response was
not due to autocrine cytokine secretion with subsequent autostimulation of the secreting cells or to UV-induced growth factor receptor activation. Cells unable to repair UVC-induced DNA damage responded to
lower doses of UVC with an even greater accumulation of
c-fos and Kin17 mRNAs than repair-proficient wild-type
cells, suggesting that a process in which a repair protein is involved
regulates mRNA stability. Although resembling the induction of p53, a
DNA damage-dependent increase in p53 was not a necessary intermediate in the stabilization reaction, since cells derived from p53 knockout mice showed the same pattern of c-fos and Kin17 mRNA
accumulation as wild-type cells. The data indicate that the signal flow
induced by UV radiation addresses not only protein stability (p53) and transcription but also RNA stability, a hitherto-unrecognized level of
UV-induced regulation.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
B target genes are activated with a delay of about 2 h
(6, 44). Since several of the response genes carry out
regulatory functions themselves (e.g., c-fos), secondary
response genes are transcribed with considerable delay (6, 9,
58). Transcriptional activation of the immediate response genes
is triggered through signal transduction which originates from one of
several primary UV target molecules (for a review, see reference 31). UV can induce signal transduction cascades
through DNA lesions introduced through irradiation (9, 46, 47,
58), through damaged ribosomal RNA (34), and through
the inactivation of one of many oxidation-sensitive protein tyrosine
phosphatases (29, 41).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
/ mouse embryo
fibroblasts, p53+/+ mouse embryo fibroblasts
(p53/ and p53+/+ [22]),
and CB17 cells were obtained from Michael Fritsche, Freiburg,
Germany; p53/mdm2/ double knockout
cells were obtained from David Lane, Dundee, Scotland; primary 
XPA
NIH 3T3 (XPA) and XPA+ NIH 3T3 (wild-type) cells were obtained from
Harry van Steeg, Bilthoven, The Netherlands; and
c-fos/ and c-fos+/+
murine embryonic fibroblasts were obtained from Peter Angel, Heidelberg, Germany.
[IL-1], 2 ng/ml), and 4 µM methyl methansulfonate (MMS), or phorbol ester
(12-O-tetradecanoyl-phorbol-13-acetate [TPA], 60 ng/ml)
were directly added to the culture medium. Treatment with gamma
irradiation was as follows: cells in culture medium were exposed to 5 Gy of radiation in a cobalt-60 gamma radiation source at a dose rate of
5.75 Gy/min. A stock solution of suramin (final concentration, 0.3 mM)
was freshly prepared in H2O and diluted into the culture
medium 30 min prior to treatment of cells. For the RNA stability assay,
cells were UVC irradiated with a dose of 30 J/m2. After a
45-min or 4.5-h incubation period, actinomycin D-mannitol (Sigma)
solubilized in water was added to the cultures to a final concentration
of 5 µg/ml and incubated further, as indicated.
RNA preparation, Northern blots, and cDNA probes.
Poly(A)+ RNA was isolated according to the method of
Rahmsdorf et al. (50), resolved on a 1.4%
agarose-formaldehyde gel, and transferred onto a Hybond N+ nylon
membrane. Hybridization was performed as previously described
(50) using radiolabelled cDNA probes comprising either an
~1,000-bp PstI fragment of v-fos (19), an ~1,000-bp fragment of mouse Kin17 obtained by PCR
with oligonucleotides 5'-GAGCCCCAAGGCCATCGCCAAT-3' and
5'-TTCCTGCGTCTCAACTTCCATA-3' (39), cDNAs of
c-jun, IB, c-myc, urokinase-type plasminogen activator (u-PA), and EF-1, or an ~1,200-bp PstI fragment
of GAPDH (25).
Metabolic labelling and immunoprecipitation. Cells were grown in DMEM without methionine and cysteine, supplemented with 8% dialyzed FCS and pulse-labelled with 150 µCi of Pro-mix (Amersham) per ml, for 2 h. Cells were washed twice in ice-cold PBS and lysed on ice in ice-cold radioimmunoprecipitation assay (RIPA) buffer (50 mM Tris [pH 8], 125 mM NaCl, 0.5% IGEPAL- CA630, 0.5% sodium desoxycholate, 0.1% sodium lauryl sulfate, 1 µg of aprotinin per ml, 1 µg of leupeptin per ml, 1 mM phenylmethylsulfonyl fluoride). The lysate was centrifuged at 150,000 × g and 4°C for 20 min. The lysate was precleared by incubation with 2 µl of a preimmune serum and protein A-agarose (Calbiochem). The resulting supernatant was added to 2 µl of a rabbit polyclonal anti-Fos antiserum precoupled to protein A-agarose. Immunoprecipitation reactions were incubated on a rocking platform at 4°C for 1.5 h. The agarose-antibody-Fos complexes were collected by centrifugation, washed four times in RIPA buffer, resuspended in sample buffer, and resolved by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (8). The gel was fixed in 30% methanol-10% acetic acid for 20 min, washed in water for 20 min, and enhanced in 1 M sodium salicylate-30% methanol for 20 min. The gel was dried and put on X-ray film for exposure.
Run-on analysis.
Isolation of nuclei and in vitro
transcription was performed according to the procedure outlined in
reference 28. After the transcription reaction was
performed, the nuclei were lysed in solution D (4 M
guanidinium-isothiocyanate, 0.5% N-laurylsarcosine, 25 mM
Na citrate, 143 mM 
-mercapthoethanol). A 1/10 volume of 2 M Na
acetate, pH 4, was added, and the reaction was vortexed. An equal
volume of phenol was added, vortexed, followed by a 1/10 volume of
chloroform, agitated, and incubated on ice for 15 min. Phases were
separated by centrifugation at 15,000 × g for 20 min, and the upper phase was mixed with an equal volume of isopropanol and
centrifuged at 15,000 × g for 15 min. The resulting
pellet was solubilized in 300 µl of solution D, and the radioactive
RNA was precipitated with an equal volume of isopropanol and washed with 70% ethanol.
MTT assay. MTT (dimethylthiazolyldiphenyltetrazolium bromide) is reduced to formazan by mitochondrial respiratory enzymes. This reaction correlates with cell viability and can be quantified spectrophotometrically.
Cells were irradiated with UVC and counted, and 103 cells/well were plated in 96-well plates in 50 µl of DMEM. After 36 h or 5 days, respectively, 50 µl of MTT freshly solubilized in DMEM at a concentration of 2 mg/ml was added, and the cells were returned to the incubator for an additional 4 h. The reaction was stopped by removing the medium and adding 50 µl of 100% isopropanol to the cells. The degree of MTT conversion was measured immediately at 590 nm.| |
RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Two waves of UVC-induced c-fos mRNA accumulation in
murine fibroblasts.
Several UV-responsive genes, e.g., those
coding for metalloproteases or plasminogen activator, are
transcriptionally activated with considerable delay (31,
47). Their transcription depends on the presence of AP-1
(Fos-Jun) binding sites, and UV-induced transcription can be prevented
by antisense depletion of Fos or Jun (57). Murine
c-fos/ cells do not respond to UVC with
transcriptional activation of the genes encoding collagenase 1, stromelysin 1, or stromelysin 3 (59). The late requirement
for AP-1 in the UVC-induced transcriptional activation of
AP-1-dependent genes contrasts with the rapid and transient kinetics of
c-Fos and c-Jun synthesis. Apparently, a second condition must be met
for metalloprotease transcription which is not established at the time
of the early Fos and Jun peak of synthesis, that is, at times when Fos
and Jun of the initial expression period should be depleted by
turnover. This second condition must occur later. We therefore wondered
which AP-1 molecules would then act on these promoters at late time points.
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), TPA, gamma irradiation, and MMS. Representative Northern blots were scanned with a laser densitometer and plotted (Fig.
2).
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The second wave of c-fos mRNA abundance and the
accumulation of Kin17 mRNA are due to UV-induced transcript
stabilization.
The immediate-early induction of c-fos
is transcriptional. To investigate whether the 8-h peak of
c-fos mRNA accumulation also depended on an elevated
transcriptional rate, we performed nuclear run-on analyses at early and
late time points after UVC irradiation. Only an early increase in rate
was detected in these analyses (Fig. 3).
Obviously, transcriptional rate is not significantly increased late
after UV irradiation. Kin17-promoter-luciferase constructs failed to
show UV-induced transcription above basal levels (data not shown), also
suggesting that UV did not increase the transcriptional rate. The
observed increases in RNA abundance (Fig. 1A) must therefore be
regulated on a posttranscriptional level.
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Several mRNAs with relatively short half-lives are stabilized by
UV.
UV-induced stabilization addresses two species of RNA with
rather different half-lives. An obvious question is how specific is
this stabilization process? We examined a series of other UV-responsive genes and found that they fall into two classes: c-jun,
c-myc, and IB RNAs were also stabilized (Fig.
5). These RNAs have in common a
relatively short spontaneous half-life of 15 to 30 min (Fig. 5). u-PA
RNA (Fig. 5) and the RNA for the translation elongation factor 1 (EF-1)
(data not shown) were not stabilized. We conclude that UV causes an
increase in lifetime for several, but not all, mRNAs.
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UVC-induced RNA stabilization is independent of secreted growth factors or of growth factor receptors. The immediate-early transcriptional activation of c-fos by UVC has been shown to depend, at least in part, on the ligand-independent activation of receptor tyrosine kinases and other receptors (4, 18, 33, 52, 55, 61). Experimental evidence included (i) UV-induced tyrosine autophosphorylation of several receptor tyrosine kinases (41, 55) and receptor clustering (4, 52), (ii) inhibition of the UV response by the growth factor receptor poison suramin, (iii) growth factor-induced downregulation of growth factor receptors and subsequent transient refractoriness either to the same growth factor or to UV (33, 55), and (iv) the inhibition of the UV response upon introduction of dominant negative versions of certain receptor tyrosine kinases (55). We aimed at obtaining similar types of evidence for the UV-induced stabilization.
As expected, pretreatment of cells with suramin for 30 min completely inhibited early c-fos mRNA accumulation (Fig. 6). This is in agreement with the previous finding that growth factor receptors are activated by UVC. Suramin could not, however, prevent UV-induced stabilization of c-fos mRNA (the second peak of RNA abundance) or the basal synthesis or the induction of Kin17 RNA at 8 h after UVC irradiation (Fig. 6). Thus, while clearly the early transcriptional induction of c-fos was suramin sensitive, RNA stabilization did not depend on activation of a suramin-sensitive receptor tyrosine kinase. At the same time, the suramin experiment rules out the possibility that the late stabilization of RNA was caused by the induced secretion of a growth factor, since its action would also be poisoned by suramin; this would have been a realistic possibility, since growth factor secretion can indeed be triggered by irradiation of cells with UVC (6, 42, 54). Participation of a secreted growth factor was also made unlikely by an experiment with serum-starved cells and hourly medium changes (see Fig. 8, lower panel). Late c-fos RNA accumulation was barely affected by medium exchange.
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, and bFGF have previously been shown to be relevant for
the UV response in cultured HeLa cells (55). This is also
the case for the early response in NIH 3T3 cells (Fig. 7A). The late
response was, however, not altered in cells pretreated with EGF,
IL-1, and bFGF (Fig. 7B), suggesting either that another secreted
(and suramin-resistant) cytokine was responsible or that
receptor-dependent pathways were not involved in UV-induced RNA
stabilization. Only the latter possibility is compatible with the
suramin experiment.
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Different UVC dose requirements for c-fos and Kin17 mRNA stabilization in cells deficient or proficient in the xpa gene. UVC affects several primary target molecules relevant for gene regulation. We ruled out receptor tyrosine kinases by the experiments described in the previous paragraph. Several late cellular reactions to UVC irradiation observed earlier appear to depend on UVC-induced DNA damage: e.g., the stabilization of p53 protein (45, 71), the release of cytokines (6), and the late transcriptional activation of several genes encoding proteases and of the metallothionein 2A gene (9, 58). That these reactions require prior UVC-induced DNA damage has been deduced from the finding that human cells deficient in the repair of UVC-induced DNA damage, such as cells derived from patients with XPA or Cockayne's syndrome, activated these functions at much lower UVC doses than did normal wild-type cells. After UV irradiation, cells from normal human individuals or mice remove by nucleotide excision repair UV-induced 6-4 photoproducts and cyclobutane pyrimidine dimers from DNA with half-lives of 90 min and 4 h, respectively (26). In particular, cells from patients with a deficiency in the xpa gene or from mice with a disruption of this gene do not repair at any measurable rate. After the initially identical deposit of UV-induced DNA damage, the density of lesions will progressively divert between normal and repair-deficient cells. To reach the same density of lesions at a given time after irradiation, a higher dose must be applied to normal cells than to repair-deficient cells. Thus, photoproduct-dependent processes will occur at a lower dose in repair-deficient cells than in wild-type cells (9).
To investigate whether the late wave of c-fos mRNA accumulation and the induction of Kin17 mRNA, like the stabilization of p53 protein (45), depended on the capacity of cells to repair UVC-induced DNA damage, we made use of 3T3 cells (designatedXPA) derived from mice in which the murine homologue of the human
xpa gene had been knocked out by recombinational
inactivation (21), and 3T3 cells from their
XPA+/+ siblings. We first confirmed that UVC induced the
second wave of c-fos mRNA induction and Kin17 mRNA induction
in XPA cells and then tested the dose dependence for RNA
stabilization (Fig. 9). Doses above 20 to
30 J/m2 were needed for stabilization of both
c-fos and Kin17 RNA in repair-proficient wild-type cells.
Only 5 to 10 J/m2 were required for half-maximal induction
in the repair-deficient XPA cells (Fig. 9). At UVC doses above 10 J/m2, Kin17 mRNA disappeared in preference over
c-fos RNA. We have no definitive explanation for this
difference. Possibly the primary transcript of Kin17 is much larger
than that of c-fos, and thus higher UV doses may
preferentially affect basal Kin17 transcription by a DNA
lesion-dependent block of elongation. From the dose-response curves
shown in Fig. 9, we can conclude either that UVC-induced DNA lesions
are intermediates in the induced stabilization of c-fos and
Kin17 RNAs or that components of the XPA complex affect RNA stability.
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/ [22]) (Fig. 10), excluding a role
for p53 in UVC-induced c-fos and Kin17 RNA stabilization.
Also, cells doubly negative for p53 and Mdm2 responded like wild-type
cells, with two peaks of c-fos RNA (results not shown),
indicating that Mdm2 also has no role in the stabilization process.
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Delayed death of c-fos/ cells.
Fos
is the subunit of a transcription factor, AP-1, which is decisive for a
large number of genes. In its absence, the UV response of several genes
is hampered (59). The induction of c-fos
transcription and of RNA stabilization could establish a survival
advantage. Along these lines of thought,
c-fos/ cells have been examined for survival
after UV irradiation. Indeed, c-fos/ cells
were found to be less resistant to UV (measured by lactic dehydrogenase
release), an effect not accounted for by a difference of DNA repair
(59). We have confirmed this result using a different survival assay, the MTT conversion assay, which measures viability instantaneously (Fig. 11).
Interestingly, viability of c-fos/ cells was
decreased with an enormous delay: at 36 h, MTT counts were still
normal, while decreasing progressively thereafter.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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This paper describes a novel feature of c-fos
regulation, UV-induced stabilization of its RNA
surprising in view of
the fact that many laboratories (including one of ours) have studied
c-fos for years. UV-induced stabilization of RNA appears to
be selective: the RNAs for c-fos, c-jun,
c-myc, IB, and Kin17 (this paper) are stabilized,
whereas actin, GAPDH (see Fig. 4), u-PA, and EF-1 RNA turnover was not
changed (data not shown and this paper). Stabilization of RNA can, of
course, only occur with RNA that is intrinsically unstable.
Nevertheless, both Kin17 and u-PA show moderately long half-lives but
are discriminated by the stabilization process. The magnitude and time
course of stabilization depend on the rate of transcription and
therefore vary with different genes. The spontaneous transcription of
c-fos and c-jun is a function of growth
conditions and likely differs between cell types. A low transcriptional
rate in several human cell lines may be the reason that UVC-induced
c-fos RNA stabilization in these cells was barely detectable.
UVC-induced RNA stabilization varied with the capacity of cells to repair photoproducts in nuclear DNA. In repair (XPA)-deficient fibroblasts, a two- to three-times-lower UV dose was required for RNA stabilization than in repair-proficient cells. This observation supports our hypothesis that the density of DNA lesions (and of protein complexes assembled at these lesions) is an intermediate in induced RNA stabilization, as lesion density remains constant in XPA cells, while wild-type cells remove lesions with a half-life of 90 min to 4 h (26). To retain the same lesion density in repair-proficient cells, the initial dose applied must be higher in repair-proficient cells. Alternative explanations for the different dose responses in XPA and wild-type cells need to be considered (see below).
Following the DNA damage hypothesis, it is obvious that additional steps are required between the introduction of DNA lesions and the activation or inactivation of critical proteins affecting RNA stability. A hypothetical scheme could involve a lesion-dependent arrest of transcription which is converted in an unknown fashion into a signaling pathway to the RNA-degrading exosome (67). Indeed, transcriptional induction of genes and stabilization of p53 correlate best with DNA lesions in transcribed regions of the genome (9, 71). To identify components of a signal transduction chain involved in the UV-dependent stabilization of RNA, we tested numerous inhibitors. None, however, prevented the stabilization: vanadate, SB203580 (Jun N-terminal protein kinases [JNKs] and p38), PD98059 and U0126 (MEKs), Ly294002 (phosphatidylinositol 3-kinases, ATM, and DNA-dependent protein kinase), wortmannin, rapamycin (S6 kinase), roscovitin (CDKs), okadaic acid (protein phosphatase 2A), H7 (protein kinase C), trichostatin (histone deacetylase), and several inhibitors of protein synthesis. Tentatively, this also excludes the involvement of known protein kinases recognizing DNA strand breaks.
RNAs regulated by changes in turnover carry specific cis-acting elements. One of these elements, consisting of several repeats of the sequence AUUUA, is found in the 3' UTR (16, 36, 53). Indeed, c-fos, c-jun, c-myc, and Kin17 RNAs carry AUUUA repeats in their 3' UTRs. These AU-rich sequences bind several specific proteins, one of which clearly increases RNA stability (49). Also, cis-acting elements in other sites of the mature RNA likely bind specific proteins, affecting RNA stability. We hypothesize that a signal transduction cascade originating from a DNA photoproduct leads to activation of RNA binding proteins involved in RNA stability. Interestingly, JNK can prolong the lifetime of IL-2 RNA (17). If JNK were activated by DNA damage (which is still debated [1]), UV-induced JNK activity would be a good candidate as a member of the signal transduction cascade. Inhibitor studies, however, speak against a role by JNK.
Could cells defective in XPA lack repair of some other cellular component damaged by UV? We are not aware of another XPA-dependent repair process but cannot exclude its existence. For instance, double-stranded RNA, e.g., in ribosomes, could be subjected to XPA-dependent lesion repair. Damage to ribosomal RNA has been reported to cause signal transduction to JNK (34). One could also argue that the increased response in XPA cells reflects release from an RNA turnover process, suggesting that XPA and partner proteins were actively involved in mediating high rates of RNA turnover. This involvement would need to occur only after UV irradiation. UV irradiation could then be absorbed by a relevant non-DNA and/or non-RNA target. But we find difficult to explain, in this hypothetical scheme, the dose difference of UV-induced RNA stabilization between XPA and wild-type cells.
Could a transcriptional factor be involved in RNA stabilization? It is puzzling that the activation of several transcription factors not only affects transcription but also the turnover of their target transcripts: e.g., the estrogen receptor (13), glucocorticoid receptor (48), and p53 (27). To our knowledge, the mechanisms of how transcription factors could achieve RNA stabilization are not clear. One could argue that, at the same time, they transcribe genes whose products participate in RNA metabolism.
p53 is an interesting candidate for the stabilization of
c-fos and Kin17 RNA as well as other stress-induced RNAs
(35), since p53 is rescued from rapid proteasome-dependent
degradation by a DNA damage-dependent mechanism (5, 14).
Furthermore, p53 has been reported to induce RNA stability of its
transcriptional target gene, p21WAF-1
(27). Moreover, c-fos (but not Kin17) is also a
target gene of the transcription factor p53 (23 and
our unpublished data). However, several arguments speak against a
participation of p53 in UV-dependent c-fos and Kin17 RNA
stabilization: (i) p53 levels in cells are increased by both UV and
X-ray treatment, whereas c-fos and Kin17 RNA stability is
induced only by UV. (ii) p21 RNA turnover regulation by p53 is under
tyrosine kinase-phosphatase control in the absence of p53, as shown by
the effect of vanadate (27). Vanadate had no effect on
UVC-induced c-fos and Kin17 RNA stabilization (as discussed
above). (iii) UV-induced RNA stabilization occurs in both
p53+/+ and p53/ cells.
Although stabilization of c-fos RNA does not involve p53,
p53 does interact in an interesting way with the transcription factor AP-1, which contains Fos and Jun as subunits. As shown by the comparison of Jun+/+ and Jun/ cells, p53
synthesis is repressed by a Jun-containing member of the AP-1 family
(60). p53, in turn, induces immediate-early c-fos
transcription by binding to an intronic p53 binding site (23), detected by activating a temperature-sensitive p53
mutant protein.
A simple interpretation of the UV effect on RNA stability could be that
the overall inhibition of transcription and translation by UVC
preferentially affected the availability of an RNA-degrading enzyme. In
fact, the inhibition of translation by cycloheximide indeed stabilizes
c-fos RNA (50), and UVC treatment of cells leads
to the disappearance of specific proteins, e.g., the oncoprotein Mdm2
(10, 70). The stabilization of c-fos and Kin17
RNA occurs under irradiation conditions which reduce overall
transcription, due to the arrest of elongation at sites of DNA lesions.
One could speculate that the physiological significance of RNA
stabilization represents a rescue mechanism for important survival
functions which are (for example) AP-1 and NF-B (6)
dependent. This is compatible with the observed survival-promoting
action of Fos (59 and this paper).
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ACKNOWLEDGMENTS |
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We are grateful to Helmut Ponta and Martin Göttlicher for text and figure criticism.
This work was supported by the European Community (grant F14P-CT96-0052) and by the Association pour la Recherche sur le Cancer (contract no. 6060) and Electricité de France (contract no. 8702). P. Kannouche received a fellowship from the Institut National de la Science et la Technologie Nucléaire (INSTN) du CEA and from EDF.
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FOOTNOTES |
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* Corresponding author. Mailing address: Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, P.O. Box 3640, 76021 Karlsruhe, Germany. Phone: 49-7247-823292. Fax: 49-7247-823354. E-mail: genetik{at}igen.fzk.de.
Present address: Cancer Research Campaign, Cell Transformation
Research Group, Department of Biochemistry, Medical Sciences Institute,
University of Dundee, Dundee DD1 4HN, United Kingdom.
Present address: Medical Research Council, Cell Mutation Unit,
Sussex University, Falmer, Brighton BN1 9RR, United Kingdom.
§ Present address: Institut für Rechtsmedizin, Am Pulverturm 3, 55131 Mainz, Germany.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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