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Cancer Res. 2010 Mar 1;70(5):1854-65. doi: 10.1158/0008-5472.CAN-09-1922. Epub 2010 Feb 23.

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

Author information

1
Department of Pathology and Laboratory Medicine, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.

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.

PMID:
20179200
PMCID:
PMC2831128
DOI:
10.1158/0008-5472.CAN-09-1922
[Indexed for MEDLINE]
Free PMC Article

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