Re-expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1arrest associated with induction of p16ink4a and activation of RB

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Abstract

Truncating mutations and homozygous deletions in the hSNF5/INI1/BAF47 subunit of human SWI/SNF complexes occur in most malignant rhabdoid tumors and some other malignancies. How loss of hSNF5 contributes to tumorigenesis remains unknown. Because the SWI/SNF subunit BRG1 is required for RB-mediated cell cycle arrest, we hypothesized that hSNF5 deficiency disrupts RB signaling. Here we demonstrate that unlike BRG1, hSNF5 deficient cells retain functional RB since ectopic expression of either p16ink4a or a constitutively active form of RB (PSM–RB) led to cell cycle arrest. To determine how hSNF5 loss might contribute to tumorigenesis, we used a retrovirus to introduce hSNF5 into multiple deficient cell lines. In all cases, re-expression inhibited colony formation and induced cell cycle arrest characterized by a flattened morphology. Flow cytometry revealed that these cells accumulated in G0/G1. Importantly, arrested cells exhibited strong induction of p16ink4a, hypophosphorylated RB, and down-regulation of cyclin A, suggesting that hSNF5 signals upstream of RB to induce growth arrest. Co-expression of SV40 T/t abolished hSNF5-induced G1arrest and activation of RB. Likewise, HPV-16 E7 was sufficient to partially overcome cell cycle arrest. These results suggest that hSNF5 loss is not equivalent to BRG1/BRM loss in human tumor cell lines. Furthermore, hSNF5-induced cell cycle arrest of deficient cells is mediated in part through activation of p16ink4a expression. These findings provide insight into mechanisms of hSNF5-mediated tumor suppression.

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Correspondence to Bernard E Weissman.

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Betz, B., Strobeck, M., Reisman, D. et al. Re-expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1arrest associated with induction of p16ink4a and activation of RB. Oncogene 21, 5193–5203 (2002) doi:10.1038/sj.onc.1205706

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Keywords

  • rhabdoid
  • SWI/SNF
  • hSNF5/INI1/BAF47
  • RB
  • p16ink4a

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