Reexpression of hSNF5 in malignant rhabdoid tumor cell lines causes cell cycle arrest through a p21(CIP1/WAF1)-dependent mechanism.

Abstract:

:Loss of hSNF5 function is usually observed in malignant rhabdoid tumor (MRT), a highly aggressive pediatric neoplasm. Previous studies have shown that reexpression of hSNF5 in MRT cell lines causes G1 cell cycle arrest with p16(INK4A), p21(CIP1/WAF1), and cyclin D1 playing key roles in MRT cell growth control. However, we have shown that reexpression of hSNF5 induced cell cycle arrest in the absence of p16(INK4A) expression. These results indicate that the mechanism of hSNF5-induced cell cycle arrest is context dependent. Here, we investigated the relationship between p21(CIP1/WAF1) and hSNF5 in the regulation of growth using several MRT cell lines. We found that G1 cell cycle arrest occurred concomitant with an increase in p21(CIP1/WAF1) mRNA and protein levels and preceded p16(INK4A) mRNA and protein upregulation. Chromatin immunoprecipitation data confirmed that hSNF5 appeared at both p21(CIP1/WAF1) and p16(INK4A) promoters after reexpression. We further showed that p21(CIP1/WAF1) induction showed both p53-dependent and p53-independent mechanisms. We also showed that reduction of p21(CIP1/WAF1) expression by RNAi significantly inhibited hSNF5-induced G(1) arrest. Our results show that both p21(CIP1/WAF1) and p16(INK4A) are targets for hSNF5 and that p21(CIP1/WAF1) upregulation during hSNF5-induced G(1) arrest precedes p16(INK4A) upregulation. These findings indicate that SNF5 mediates a temporally controlled program of cyclin-dependent kinase inhibition to restrict aberrant proliferation in MRT cells.

journal_name

Cancer Res

journal_title

Cancer research

authors

Kuwahara Y,Charboneau A,Knudsen ES,Weissman BE

doi

10.1158/0008-5472.CAN-09-1922

subject

Has Abstract

pub_date

2010-03-01 00:00:00

pages

1854-65

issue

5

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-09-1922

journal_volume

70

pub_type

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