Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation.
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.
Isakoff
Michael S
MS
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Sansam
Courtney G
CG
Tamayo
Pablo
P
Subramanian
Aravind
A
Evans
Julia A
JA
Fillmore
Christine M
CM
Wang
Xi
X
Biegel
Jaclyn A
JA
Pomeroy
Scott L
SL
Mesirov
Jill P
JP
Roberts
Charles W M
CW
D000818:Animals; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D020869:Gene Expression Profiling; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011123:Polyploidy; D018335:Rhabdoid Tumor / Q000235:genetics / Q000473:pathology; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C513265:Smarcb1 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53