Regulation of H-ras splice variant expression by cross talk between the p53 and nonsense-mediated mRNA decay pathways.
When cells are exposed to a genotoxic stress, a DNA surveillance pathway that involves p53 is activated, allowing DNA repair. Eukaryotic cells have also evolved a mechanism called mRNA surveillance that controls the quality of mRNAs. Indeed, mutant mRNAs carrying premature translation termination codons (PTCs) are selectively degraded by the nonsense-mediated mRNA decay (NMD) pathway. However, in the case of particular genes, such as proto-oncogenes, mutations that do not create PTCs and therefore that do not induce mRNA degradation, can be harmful to cells. In this study, we showed that the H-ras gene in the absence of mutations produces an NMD-target splice variant that is degraded in the cytosol. We observed that a treatment with the genotoxic stress inducer camptothecin for 6 h favored the production of the H-ras NMD-target transcript degraded in the cytosol by the NMD process. Our data indicated that the NMD process allowed the elimination of transcripts produced in response to a short-term treatment with camptothecin from the major proto-oncogene H-ras, independently of PTCs induced by mutations. The camptothecin effects on H-ras gene expression were p53 dependent and involved in part modulation of the SC35 splicing factor. Interestingly, a long-term treatment with camptothecin as well as p53 overexpression for 24 h resulted in the accumulation of the H-ras NMD target in the cytosol, although the NMD process was not completely inhibited as other NMD targets are not stabilized. Finally, Upf1, a major NMD effector, was necessary for optimal p53 activation by camptothecin, which is consistent with recent data showing that NMD effectors are required for genome stability. In conclusion, we identified cross talk between the p53 and NMD pathways that regulates the expression levels of H-ras splice variants.
Barbier
Jérôme
J
INSERM U685, Equipe AVENIR, Hopital Saint-Louis, 1 Avenue Claude Vellefaux, Paris 75010, France.
Dutertre
Martin
M
Bittencourt
Danielle
D
Sanchez
Gabriel
G
Gratadou
Lise
L
de la Grange
Pierre
P
Auboeuf
Didier
D
D017398:Alternative Splicing; D002166:Camptothecin / Q000378:metabolism; D002458:Cell Fractionation; D002460:Cell Line; D018389:Codon, Nonsense; D003593:Cytoplasm / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005786:Gene Expression Regulation; D011905:Genes, ras; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D020365:RNA Helicases; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D059004:Topoisomerase I Inhibitors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D018389:Codon, Nonsense; C000715470:MAS1 protein, human; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D020365:RNA Helicases; C101828:UPF1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D004264:DNA Topoisomerases, Type I; D002166:Camptothecin
Int J Oncol. 1998 Apr;12(4):793-804
9499438
Nature. 1996 May 2;381(6577):80-2
8609994
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9155-60
9689050
Cell Death Differ. 2005 Jun;12(6):687-9
15775998
Nucleic Acids Res. 2005;33(13):4276-84
16052034
Genomics. 2005 Sep;86(3):329-36
16005179
Nat Med. 2005 Sep;11(9):920-2
16145569
Nucleic Acids Res. 2005;33(16):5053-62
16147989
Mol Cell. 2005 Oct 7;20(1):65-75
16209946
Genes Dev. 2006 Jan 15;20(2):153-8
16418482
Curr Biol. 2006 Feb 21;16(4):433-9
16488880
J Biol Chem. 2006 Mar 31;281(13):8707-15
16436381
Nat Rev Mol Cell Biol. 2006 Jun;7(6):415-25
16723977
Sci STKE. 2006 May 30;2006(337):pe24
16738062
Cell. 2006 Jul 14;126(1):37-47
16839875
Nat Rev Cancer. 2006 Oct;6(10):789-802
16990856
Trends Biochem Sci. 2006 Nov;31(11):639-46
17010613
Oncogene. 2006 Nov 2;25(52):6936-47
16983332
Cancer Res. 2006 Dec 15;66(24):11817-24
17178878
PLoS Biol. 2007 May;5(5):e109
17456004
Int J Oncol. 1999 Nov;15(5):861-71
10536167
J Cell Biol. 2000 Apr 17;149(2):307-16
10769024
RNA. 2000 Jul;6(7):962-75
10917593
EMBO J. 2000 Sep 1;19(17):4734-44
10970865
Oncogene. 2000 Nov 30;19(51):5831-41
11127813
RNA. 2001 Jan;7(1):5-15
11214180
Cell. 2000 Dec 22;103(7):1121-31
11163187
EMBO J. 2001 Apr 2;20(7):1785-96
11285241
Oncogene. 2001 Mar 8;20(10):1212-9
11313865
Mol Cell Biol. 2001 Aug;21(16):5512-9
11463833
Cancer Res. 2001 Sep 15;61(18):6876-84
11559564
Mol Cell Biol. 2002 May;22(10):3497-508
11971980
J Biol Chem. 2002 May 24;277(21):18489-93
11889124
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8467-72
12077306
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):189-92
12502788
Mol Cell Biol. 2003 Apr;23(8):2927-41
12665590
Nat Rev Cancer. 2003 Jun;3(6):459-65
12778136
Nucleic Acids Res. 2003 Jul 1;31(13):3568-71
12824367
Cancer Res. 2003 Sep 1;63(17):5178-87
14500341
Exp Cell Res. 2003 Nov 15;291(1):176-88
14597418
Cancer Res. 2003 Dec 1;63(23):8203-11
14678976
Mol Cancer Res. 2004 Jan;2(1):53-61
14757846
Nat Rev Mol Cell Biol. 2004 Feb;5(2):89-99
15040442
Mol Cell. 2004 Jun 4;14(5):585-98
15175154
DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1049-56
15279792
Nat Genet. 2004 Aug;36(8):801-8
15284851
Biochem Biophys Res Commun. 2004 Nov 5;324(1):186-92
15465000
EMBO J. 1992 Sep;11(9):3271-8
1324170
J Biol Chem. 1995 Dec 1;270(48):28995-9003
7499432
RNA. 1998 Apr;4(4):430-44
9630249