The tumor suppressor hSNF5/INI1 modulates cell growth and actin cytoskeleton organization.
hSNF5/INI1, which encodes a component of the ATP-dependent chromatin remodeling hSWI-SNF complex, is a tumor suppressor gene mutated in malignant rhabdoid tumors. We have developed a tetracycline-based hSNF5/INI1-inducible system in a hSNF5/INI1-deficient malignant rhabdoid tumor cell line and studied time course variation of 22,000 genes/expressed sequence tags upon hSNF5/INI1 induction. A total of 482 responsive genes were identified and further clustered into 9 groups of coregulated genes. Among genes with early and strong inductions, the use of a fusion protein with the hormone-binding domain of the estrogen receptor enabled the identification of a subset of direct targets regulated independently of de novo protein synthesis. We show that the G(1) arrest induced by hSNF5/INI1 is reversible and associated with the down-regulation of components of the DNA replication complex. We also identify an unsuspected role of hSNF5/INI1 in cytoskeleton organization. Indeed, induction of hSNF5/INI1 induces dramatic modifications of the cell shape including complete disruption of the actin stress fiber network and disappearance of focal adhesions associated with up-regulation of genes involved in the organization of the actin cytoskeleton. We document a strong decrease of Rho activity upon hSNF5/INI1 expression, suggesting that the regulation of this activity constitutes a crucial step of the hSNF5/INI1-induced reorganization of the actin network. This study identifies hSNF5/INI1 target genes and provides evidence that hSNF5/INI1 may modulate the cell cycle control and cytoskeleton organization through the regulation of the retinoblastoma protein-E2F and Rho pathways.
Medjkane
Souhila
S
INSERM U509, Laboratoire de Pathologie Moléculaire des Cancers, Institut Curie, Paris, France.
Novikov
Eugene
E
Versteege
Isabella
I
Delattre
Olivier
O
D000199:Actins / Q000378:metabolism / Q000502:physiology*; D000595:Amino Acid Sequence; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone; D003599:Cytoskeleton / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D018335:Rhabdoid Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071796:SMARCB1 Protein; D014157:Transcription Factors; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D000199:Actins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D020741:rho GTP-Binding Proteins