Article

P16INK4a is required for hSNF5 chromatin remodeler-induced cellular senescence in malignant rhabdoid tumor cells

Molecular Cell Biology Group , Leiden University, Leyden, South Holland, Netherlands
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2004; 279(5):3807-16. DOI: 10.1074/jbc.M309333200
Source: PubMed

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 G(0)/G(1), induces cellular senescence and increased apoptosis. Following hSNF5 expression, we observed transcriptional activation of the tumor suppressor p16(INK4a) but not of p14(ARF), repression of several cyclins and CD44, a cell surface glycoprotein implicated in metastasis. Chromatin immunoprecipitations indicated that hSNF5 activates p16(INK4a) 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 p16(INK4a) is an essential effector of hSNF5-induced cell cycle arrest. 1) Overexpression of p16(INK4a) 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 p16(INK4a) activation by siRNA blocks hSNF5-mediated cellular senescence. Collectively, these results indicate that in human MRT cells, the p16(INK4a)/pRb, rather than the p14(ARF)/p53 pathway, mediates hSNF5-induced cellular senescence.

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    • "This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors (Oruetxebarria, Venturini et al. 2004; Martinez- Glez, Franco-Hernandez et al. 2008). In addition, the LARGE gene (22q12.3) "
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    • "Indeed, loss of heterozygosity of SNF5 predisposes mice to cancer development at a high frequency (Guidi et al. 2001; Klochendler-Yeivin et al. 2000; Roberts et al. 2000). In addition, conditional inactivation of SNF5 in hematopoietic tissues resulted in an extremely rapid onset of CD8+ lymphomas (Roberts et al. 2002), potentially via transcriptional activation of p16 and inhibition of cyclin D1 (Chai et al. 2007; Oruetxebarria et al. 2004; Vries et al. 2005; Zhang et al. 2002). "
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    • "As well as contributing to large-scale heterochromatinization, hBrm might also contribute to up-regulation of specific genes that activate the senescence program. For example, hSNF5, a tumor-suppressor protein and a component of the hBrmcontaining complex, is a direct activator of p16INK4a expression (Oruetxebarria et al ., 2004). It is important to define the functional relationship between the HIRA /ASF1a histone chaperone complex and the pRB/hBrm/ HDAC1/HP1 β complex. "
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