Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

doi:10.1073/pnas.0509014102

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation

^*Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; ^†Division of Hematology/Oncology and ^**Division of Neuroscience, Department of Neurology, Children's Hospital Boston, Boston, MA 02115; ^‡Department of Pediatrics, Harvard Medical School, Boston, MA 02115; ^¶Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02141; and ^∥Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104

Communicated by Stuart H. Orkin, Harvard Medical School, Boston, MA, October 14, 2005 (received for review June 23, 2005)

Abstract

Snf5 (Ini1/Baf47/Smarcb1), a core member of the Swi/Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi/Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant up-regulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.

Footnotes

↵ †† To whom correspondence should be addressed at: Dana-Farber Cancer Institute, 44 Binney Street M657, Boston, MA 02115. E-mail: charles_roberts{at}dfci.harvard.edu.
↵ § M.S.I. and C.G.S. contributed equally to this work.
Author contributions: M.S.I. and C.W.M.R. designed research; M.S.I., C.G.S., J.A.E., C.M.F., X.W., and C.W.M.R. performed research; P.T., A.S., J.A.B., S.L.P., and J.P.M. contributed new reagents/analytic tools; P.T., A.S., and J.P.M. analyzed data; and C.W.M.R. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations: RT, rhabdoid tumor; NMF, nonnegative matrix factorization; MEF, murine embryonic fibroblast; GSEA, Gene Set Enrichment Analysis; Rb, retinoblastoma.