Abstract
SNF5, a core component of the SWI/SNF chromatin remodeling complex, is expressed as two isoforms, SNF5a and SNF5b. SNF5 is a tumor suppressor, as mutation of SNF5 leads to tumor formation and cooperates with p53 deficiency to enhance cancer susceptibility. Interestingly, lack of SNF5 inhibits cell survival and embryonic development, potentially through abnormal activation of p53. To further examine this, we generated cell lines in which SNF5a, SNF5b or both can be inducibly knocked down. We found that SNF5 knockdown leads to cell-cycle arrest in G1, and SNF5a and SNF5b are functionally redundant. We also showed that SNF5 knockdown impairs p53-dependent transcription of p21 and murine double minute 2. However, contrary to earlier reports that p53 is activated by SNF5 knockout in murine cells, SNF5 knockdown leads to decreased, but not increased, expression of both basal and stress-induced p53 in multiple human cell lines. In addition, we showed that SNF5 knockdown induces adenosine monophosphate-activated protein kinase activation and inhibits eIF4E expression. Finally, we showed that SNF5 knockdown inhibits p53 translation by eIF4E and replacement of eIF4E in SNF5 knockdown cells restores p53 expression and cell survival. Together, our study results suggest that the p53 pathway is regulated by, and mediates the activity of, SNF5 in tumor suppression and prosurvival.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Brosh R, Rotter V . (2009). When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9: 701–713.
Caramel J, Medjkane S, Quignon F, Delattre O . (2008). The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors. Oncogene 27: 2035–2044.
Carlson M, Laurent BC . (1994). The SNF/SWI family of global transcriptional activators. Curr Opin Cell Biol 6: 396–402.
Chai J, Lu X, Godfrey V, Fletcher C, Roberts CW, Van Dyke T et al. (2007). Tumor-specific cooperation of retinoblastoma protein family and Snf5 inactivation. Cancer Res 67: 3002–3009.
Chen X, Bargonetti J, Prives C . (1995). p53, through p21 (WAF1/CIP1), induces cyclin D1 synthesis. Cancer Res 55: 4257–4263.
Graff JR, Konicek BW, Carter JH, Marcusson EG . (2008). Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 68: 631–634.
Gresh L, Bourachot B, Reimann A, Guigas B, Fiette L, Garbay S et al. (2005). The SWI/SNF chromatin-remodeling complex subunit SNF5 is essential for hepatocyte differentiation. EMBO J 24: 3313–3324.
Guidi CJ, Veal TM, Jones SN, Imbalzano AN . (2004). Transcriptional compensation for loss of an allele of the Ini1 tumor suppressor. J Biol Chem 279: 4180–4185.
Guidi CJ, Sands AT, Zambrowicz BP, Turner TK, Demers DA, Webster W et al. (2001). Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice. Mol Cell Biol 21: 3598–3603.
Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS et al. (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30: 214–226.
Harms K, Nozell S, Chen X . (2004). The common and distinct target genes of the p53 family transcription factors. Cell Mol Life Sci. 61: 822–842.
Harms KL, Chen X . (2005). The C terminus of p53 family proteins is a cell fate determinant. Mol Cell Bio 25: 2014–2030.
Holstege FC, Jennings EG, Wyrick JJ, Lee TI, Hengartner CJ, Green MR et al. (1998). Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95: 717–728.
Inoki K, Zhu T, Guan KL . (2003a). TSC2 mediates cellular energy response to control cell growth and survival. Cell 115: 577–590.
Inoki K, Li Y, Xu T, Guan KL . (2003b). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17: 1829–1834.
Isakoff MS, Sansam CG, Tamayo P, Subramanian A, Evans JA, Fillmore CM et al. (2005). Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation. Proc Natl Acad Sci USA 102: 17745–17750.
Kingston RE, Narlikar GJ . (1999). ATP-dependent remodeling and acetylation as regulators of chromatin fluidity. Genes Dev 13: 2339–2352.
Klochendler-Yeivin A, Picarsky E, Yaniv M . (2006). Increased DNA damage sensitivity and apoptosis in cells lacking the Snf5/Ini1 subunit of the SWI/SNF chromatin remodeling complex. Mol Cell Biol 26: 2661–2674.
Klochendler-Yeivin A, Fiette L, Barra J, Muchardt C, Babinet C, Yaniv M . (2000). The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep 1: 500–506.
Ko LJ, Prives C . (1996). p53: puzzle and paradigm. Genes Dev 10: 1054–1072.
Lee D, Kim JW, Seo T, Hwang SG, Choi EJ, Choe J et al. (2002). SWI/SNF complex interacts with tumor suppressor p53 and is necessary for the activation of p53-mediated transcription. J Biol Chem 277: 22330–22337.
Liu G, Chen X . (2006). DNA polymerase eta, the product of the xeroderma pigmentosum variant gene and a target of p53, modulates the DNA damage checkpoint and p53 activation. Mol Cell Biol 26: 1398–1413.
Maltzman W, Czyzyk L . (1984). UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol Cell Biol 4: 1689–1694.
Martens JA, Winston F . (2003). Recent advances in understanding chromatin remodeling by Swi/Snf complexes. Curr Opin Genet Dev 13: 136–142.
McKenna ES, Sansam CG, Cho YJ, Greulich H, Evans JA, Thom CS et al. (2008). Loss of the epigenetic tumor suppressor SNF5 leads to cancer without genomic instability. Mol Cell Biol 28: 6223–6233.
Oruetxebarria I, Venturini F, Kekarainen T, Houweling A, Zuijderduijn LM, Mohd-Sarip A et al. (2004). P16INK4a is required for hSNF5 chromatin remodeler-induced cellular senescence in malignant rhabdoid tumor cells. J Biol Chem 279: 3807–3816.
Peterson CL . (1996). Multiple SWItches to turn on chromatin? Curr Opin Genet Dev 6: 171–175.
Roberts CW, Orkin SH . (2004). The SWI/SNF complex—chromatin and cancer. Nat Rev Cancer 4: 133–142.
Roberts CW, Leroux MM, Fleming MD, Orkin SH . (2002). Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell 2: 415–425.
Roberts CW, Galusha SA, McMenamin ME, Fletcher CD, Orkin SH . (2000). Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice. Proc Natl Acad Sci USA 97: 13796–13800.
Scoumanne A, Chen X . (2008). Protein methylation: a new mechanism of p53 tumor suppressor regulation. Histol Histopathol 23: 1143–1149.
Scoumanne A, Zhang J, Chen X . (2009). PRMT5 is required for cell-cycle progression and p53 tumor suppressor function. Nucleic Acids Res 37: 4965–4976.
Sevenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O . (1999a). Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 65: 1342–1348.
Sevenet N, Lellouch-Tubiana A, Schofield D, Hoang-Xuan K, Gessler M, Birnbaum D et al. (1999b). Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations. Hum Mol Genet 8: 2359–2368.
Sif S, Saurin AJ, Imbalzano AN, Kingston RE . (2001). Purification and characterization of mSin3A-containing Brg1 and hBrm chromatin remodeling complexes. Genes Dev 15: 603–618.
Sudarsanam P, Iyer VR, Brown PO, Winston F et al. (2000). Whole-genome expression analysis of snf/swi mutants of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 97: 3364–3369.
Takagi M, Absalon MJ, McLure KG, Kastan MB . (2005). Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell 123: 49–63.
Versteege I, Sévenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R et al. (1998). Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394: 203–206.
Vries RG., Bezrookove V, Zuijderduijn LM, Kia SK, Houweling A, Oruetxebarria I et al. (2005). Cancer-associated mutations in chromatin remodeler hSNF5 promote chromosomal instability by compromising the mitotic checkpoint. Genes Dev 19: 665–670.
Xu Y, Zhang J, Chen X . (2007). The activity of p53 is differentially regulated by Brm- and Brg1-containing SWI/SNF chromatin remodeling complexes. J Biol Chem 282: 37429–37435.
Zhang ZK, Davies KP, Allen J, Zhu L, Pestell RG, Zagzag D et al. (2002). Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5. Mol Cell Biol 22: 5975–5988.
Acknowledgements
This work is supported in part by NIH Grants CA081237, CA076069 and CA102188.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Xu, Y., Yan, W. & Chen, X. SNF5, a core component of the SWI/SNF complex, is necessary for p53 expression and cell survival, in part through eIF4E. Oncogene 29, 4090–4100 (2010). https://doi.org/10.1038/onc.2010.159
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.159
Keywords
This article is cited by
-
A comprehensive analysis of coding and non-coding transcriptomic changes in cutaneous squamous cell carcinoma
Scientific Reports (2020)
-
Expression and potential role of SNF5 in endometrial carcinoma
BMC Women's Health (2019)
-
Epigenomic regulation of oncogenesis by chromatin remodeling
Oncogene (2016)
-
ARID1A: a potential prognostic factor for breast cancer
Tumor Biology (2014)
-
The clinicopathologic significance of p53 and BAF-250a (ARID1A) expression in clear cell carcinoma of the endometrium
Modern Pathology (2013)