A key role of the hSNF5/INI1 tumour suppressor in the control of the G1-S transition of the cell cycle.
The hSNF5/INI1 gene encodes a member of the SWI/SNF chromatin remodelling complexes. It was recently identified as a tumour suppressor gene mutated in sporadic and hereditary Malignant Rhabdoid Tumours (MRT). However, the role of hSNF5/INI1 loss-of-function in tumour development is still unknown. Here, we show that the ectopic expression of wild-type hSNF5/INI1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into S phase of MRT cells. This G1 arrest is associated with down-regulation of a subset of E2F targets including cyclin A, E2F1 and CDC6. This arrest can be reverted by coexpression of cyclin D1, cyclin E or viral E1A, whereas it cannot be counteracted by pRB-binding deficient E1A mutants. Moreover, hSNF5/INI1 is not able to arrest cells lacking a functional pRB. These observations suggest that the hSNF5/INI1-induced G1 arrest is dependent upon the presence of a functional pRB. However, the observation that a constitutively active pRB can efficiently arrest MRT cells indicates that hSNF5/INI1, at the difference of the ATPase subunits of the SWI/SNF complex, is dispensable for pRB function. Altogether, these data show that hSNF5/INI1 is a potent regulator of the entry into S phase, an effect that may account for its tumour suppressor role.
Versteege
Isabella
I
INSERM U509, Laboratoire de Pathologie Moléculaire des Cancers, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Medjkane
Souhila
S
Rouillard
Danny
D
Delattre
Olivier
O
D001973:Bromodeoxyuridine; D018797:Cell Cycle Proteins / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D016193:G1 Phase / Q000235:genetics*; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000235:genetics*; D000071796:SMARCB1 Protein; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D016160:Retinoblastoma Protein; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D019938:Cyclin D1; D001973:Bromodeoxyuridine