p16INK4a Is Required for hSNF5 Chromatin Remodeler-induced Cellular Senescence in Malignant Rhabdoid Tumor Cells

Igor Oruetxebarria, Francesca Venturini, Tuija Kekarainen, Ada Houweling, Lobke M P Zuijderduijn, Adone Mohd-Sarip, Robert G J Vries, Rob C. Hoeben, C. Peter Verrijzer*

*Corresponding author for this work

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

The hSNF5 chromatin-remodeling factor is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). A number of studies have shown that hSNF5 re-expression blocks MRT cell proliferation. However, the pathway through which hSNF5 acts remains unknown. To address this question, we generated MRT-derived cell lines in which restoration of hSNF5 expression leads to an accumulation in G0/G1, induces cellular senescence and increased apoptosis. Following hSNF5 expression, we observed transcriptional activation of the tumor suppressor p16INK4a but not of p14ARF, repression of several cyclins and CD44, a cell surface glycoprotein implicated in metastasis. Chromatin immunoprecipitations indicated that hSNF5 activates p16INK4a transcription and CD44 down-regulation by mediating recruitment of the SWI/SNF complex. Thus, hSNF5 acts as a dualistic co-regulator that, depending on the promoter context, can either mediate activation or repression. Three lines of evidence established that p16INK4a is an essential effector of hSNF5-induced cell cycle arrest. 1) Overexpression of p16INK4a mimics the effect of hSNF5 induction and leads to cellular senescence. 2) Expression of a p16 INK4a-insensitive form of CDK4 obstructs hSNF5-induced cell cycle arrest. 3) Inhibition of p16INK4a activation by siRNA blocks hSNF5-mediated cellular senescence. Collectively, these results indicate that in human MRT cells, the p16INK4a/pRb, rather than the p14 ARF/p53 pathway, mediates hSNF5-induced cellular senescence.

Original languageEnglish
Pages (from-to)3807-3816
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number5
DOIs
Publication statusPublished - 30 Jan 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Oruetxebarria, I., Venturini, F., Kekarainen, T., Houweling, A., Zuijderduijn, L. M. P., Mohd-Sarip, A., Vries, R. G. J., Hoeben, R. C., & Verrijzer, C. P. (2004). p16INK4a Is Required for hSNF5 Chromatin Remodeler-induced Cellular Senescence in Malignant Rhabdoid Tumor Cells. Journal of Biological Chemistry, 279(5), 3807-3816. https://doi.org/10.1074/jbc.M309333200