p53 is activated by different stress and damage pathways and regulates cell biological responses including cell cycle arrest, repair pathways, apoptosis and senescence. Following DNA damage, the levels of p53 increase and via binding to target gene promoters, p53 induces expression of multiple genes including p21(CDKN1A) and mdm2. The effects of p53 on gene expression during the DNA damage response are well mimicked by overexpressing p53 under normal conditions. However, stress to the Endoplasmic Reticulum (ER) and the consequent Unfolded Protein Response (UPR) leads to the induction of the p53/47 isoform that lacks the first 40 aa of p53 and to an active suppression of p21(CDKN1A) transcription and mRNA translation. We now show that during ER stress p53 also suppresses MDM2 protein levels via a similar mechanism. These observations not only raise questions about the physiological role of MDM2 during ER stress but it also reveals a new facet of p53 as a repressor toward 2 of its major target genes during the UPR. As suppression of p21(CDKN1A) and MDM2 protein synthesis is mediated via their coding sequences, it raises the possibility that p53 controls mRNA translation via a common mechanism that might play an important role in how p53 regulates gene expression during the UPR, as compared to the transcription-dependent gene regulation taking place during the DNA damage response.

b Department of Medical Biosciences ; Umeå University ; Umeå Sweden

c RECAMO; Masaryk Memorial Cancer Institute ; Brno Czech Republic

Équipe Labellisée Ligue Contre le Cancer; Université Paris 7; INSERM UMR 1162 Génomique fonctionnelle des tumeurs solides ; Paris France

Zobrazit více v PubMed

Efeyan A, Serrano M. p53: guardian of the genome and policeman of the oncogenes. Cell Cycle 2007; 6:1006-10; PMID:17457049; http://dx.doi.org/10.4161/cc.6.9.4211 PubMed DOI

Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol 2007; 8:275-83; PMID:17380161; http://dx.doi.org/10.1038/nrm2147 PubMed DOI

El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, et al.. WAF1/CIP1 Is Induced in p53-mediated G1 Arrest and Apoptosis. Cancer Res 1994; 54:1169-74; PMID:8118801 PubMed

Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace AJ Jr. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 1992; 71:587-97; PMID:1423616; http://dx.doi.org/10.1016/0092-8674(92)90593-2 PubMed DOI

Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80:293-9; PMID:7834749; http://dx.doi.org/10.1016/0092-8674(95)90513-8 PubMed DOI

Lanigan F, Geraghty JG, Bracken AP. Transcriptional regulation of cellular senescence. Oncogene 2011; 30:2901-11; PMID:21383691; http://dx.doi.org/10.1038/onc.2011.34 PubMed DOI

Efeyan A, Collado M, Velasco-Miguel S, Serrano M. Genetic dissection of the role of p21Cip1/Waf1 in p53-mediated tumour suppression. Oncogene 2007; 26:1645-9; PMID:16964282; http://dx.doi.org/10.1038/sj.onc.1209972 PubMed DOI

Adnane J, Jackson RJ, Nicosia SV, Cantor AB, Pledger WJ, Sebti SM. Loss of p21WAF1/CIP1 accelerates Ras oncogenesis in a transgenic/knockout mammary cancer model. Oncogene 2000; 19:5338-47; PMID:11103935; http://dx.doi.org/10.1038/sj.onc.1203956 PubMed DOI

Barak Y, Juven T, Haffner R, Oren M. mdm2 expression is induced by wild type p53 activity. EMBO J 1993; 12:461-8; PMID:8440237 PubMed PMC

Barak Y, Gottlieb E, Juven-Gershon T, Oren M. Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. Gen Dev 1994; 8:1739-49; PMID:7958853; http://dx.doi.org/10.1101/gad.8.15.1739 PubMed DOI

Pant V, Xiong S, Jackson JG, Post SM, Abbas HA, Quintas-Cardama A, Hamir AN, Lozano G. The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity. Gen Dev 2013; 27:1857-67; PMID:23973961; http://dx.doi.org/10.1101/gad.227249.113 PubMed DOI PMC

Candeias MM, Malbert-Colas L, Powell DJ, Daskalogianni C, Maslon MM, Naski N, Bourougaa K, Calvo F, Fahraeus R. P53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol 2008; 10:1098-105; PMID:19160491; http://dx.doi.org/10.1038/ncb1770 PubMed DOI

Naski N, Gajjar M, Bourougaa K, Malbert-Colas L, Fahraeus R, Candeias MM. The p53 mRNA-Mdm2 interaction. Cell Cycle 2009; 8:31-4; PMID:19106616; http://dx.doi.org/10.4161/cc.8.1.7326 PubMed DOI

Malbert-Colas L, Ponnuswamy A, Olivares-Illana V, Tournillon AS, Naski N, Fahraeus R. HDMX folds the nascent p53 mRNA following activation by the ATM kinase. Mol Cell 2014; 54:500-11; PMID:24813712; http://dx.doi.org/10.1016/j.molcel.2014.02.035 PubMed DOI

Zhao L, Ackerman SL. Endoplasmic reticulum stress in health and disease. Curr Opin Cell Biol 2006; 18:444-52; PMID:16781856; http://dx.doi.org/10.1016/j.ceb.2006.06.005 PubMed DOI

Lisbona F, Hetz C. Turning off the unfolded protein response: an interplay between the apoptosis machinery and ER stress signaling. Cell Cycle 2009; 8:1643-4; PMID:19411860; http://dx.doi.org/10.4161/cc.8.11.8637 PubMed DOI

Bourougaa K, Naski N, Boularan C, Mlynarczyk C, Candeias MM, Marullo S, Fahraeus R. Endoplasmic reticulum stress induces G2 cell-cycle arrest via mRNA translation of the p53 isoform p53/47. Mol Cell 2010; 38:78-88; PMID:20385091; http://dx.doi.org/10.1016/j.molcel.2010.01.041 PubMed DOI

Pyronnet S, Dostie J, Sonenberg N. Suppression of cap-dependent translation in mitosis. Gen Dev 2001; 15:2083-93; PMID:11511540; http://dx.doi.org/10.1101/gad.889201 PubMed DOI PMC

Mlynarczyk C, Fahraeus R. Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21(CDKN1A). Nat Commun 2014; 5:5067; PMID:25295585; http://dx.doi.org/10.1038/ncomms6067 PubMed DOI

Candeias MM, Powell DJ, Roubalova E, Apcher S, Bourougaa K, Vojtesek B, Bruzzoni-Giovanelli H, Fahraeus R. Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation. Oncogene 2006; 25:6936-47; PMID:16983332; http://dx.doi.org/10.1038/sj.onc.1209996 PubMed DOI

Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H. Modulation of mammalian life span by the short isoform of p53. Gen Dev 2004; 18:306-19; PMID:14871929; http://dx.doi.org/10.1101/gad.1162404 PubMed DOI PMC

Ungewitter E, Scrable H. Delta40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCs. Gen Dev 2010; 24:2408-19; PMID:21041409; http://dx.doi.org/10.1101/gad.1987810 PubMed DOI PMC

Takahashi R, Giannini C, Sarkaria JN, Schroeder M, Rogers J, Mastroeni D, Scrable H. p53 isoform profiling in glioblastoma and injured brain. Oncogene 2013; 32:3165-74; PMID:22824800; http://dx.doi.org/10.1038/onc.2012.322 PubMed DOI PMC

Ho J, Benchimol S. Transcriptional repression mediated by the p53 tumour suppressor. Cell Death Differ 2003; 10:404-8; PMID:12719716; http://dx.doi.org/10.1038/sj.cdd.4401191 PubMed DOI

Riley KJ, Maher LJ 3rd. p53 RNA interactions: new clues in an old mystery. RNA 2007; 13:1825-33; PMID:17804642; http://dx.doi.org/10.1261/rna.673407 PubMed DOI PMC

Chen D, Zhang Z, Li M, Wang W, Li Y, Rayburn ER, Hill DL, Wang H, Zhang R. Ribosomal protein S7 as a novel modulator of p53-MDM2 interaction: binding to MDM2, stabilization of p53 protein, and activation of p53 function. Oncogene 2007; 26:5029-37; PMID:17310983; http://dx.doi.org/10.1038/sj.onc.1210327 PubMed DOI

Horn HF, Vousden KH. Cooperation between the ribosomal proteins L5 and L11 in the p53 pathway. Oncogene 2008; 27:5774-84; PMID:18560357; http://dx.doi.org/10.1038/onc.2008.189 PubMed DOI

Itahana K, Bhat KP, Jin A, Itahana Y, Hawke D, Kobayashi R, Zhang Y. Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell 2003; 12:1151-64; PMID:14636574; http://dx.doi.org/10.1016/S1097-2765(03)00431-3 PubMed DOI

Crighton D, Woiwode A, Zhang C, Mandavia N, Morton JP, Warnock LJ, Milner J, White RJ, Johnson DL. p53 represses RNA polymerase III transcription by targeting TBP and inhibiting promoter occupancy by TFIIIB. The EMBO J 2003; 22:2810-20; PMID:12773395; http://dx.doi.org/10.1093/emboj/cdg265 PubMed DOI PMC

Powell DJ, Hrstka R, Candeias M, Bourougaa K, Vojtesek B, Fahraeus R. Stress-dependent changes in the properties of p53 complexes by the alternative translation product p53/47. Cell Cycle 2008; 7:950-9; PMID:18414054; http://dx.doi.org/10.4161/cc.7.7.5626 PubMed DOI

The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated p53 mRNA structures

Alternative Mechanisms of p53 Action During the Unfolded Protein Response

p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress

p53 binds the mdmx mRNA and controls its translation