title: P16INK4a is required for hSNF5 chromatin remodeler-induced cellular senescence in malignant rhabdoid tumor cells.
abstract: The hSNF5 chromatin-remodeling factor is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). A number of studies have shown that hSNF5 re-expression blocks MRT cell proliferation. However, the pathway through which hSNF5 acts remains unknown. To address this question, we generated MRT-derived cell lines in which restoration of hSNF5 expression leads to an accumulation in G(0)/G(1), induces cellular senescence and increased apoptosis. Following hSNF5 expression, we observed transcriptional activation of the tumor suppressor p16(INK4a) but not of p14(ARF), repression of several cyclins and CD44, a cell surface glycoprotein implicated in metastasis. Chromatin immunoprecipitations indicated that hSNF5 activates p16(INK4a) transcription and CD44 down-regulation by mediating recruitment of the SWI/SNF complex. Thus, hSNF5 acts as a dualistic co-regulator that, depending on the promoter context, can either mediate activation or repression. Three lines of evidence established that p16(INK4a) is an essential effector of hSNF5-induced cell cycle arrest. 1) Overexpression of p16(INK4a) mimics the effect of hSNF5 induction and leads to cellular senescence. 2) Expression of a p16(INK4a)-insensitive form of CDK4 obstructs hSNF5-induced cell cycle arrest. 3) Inhibition of p16(INK4a) activation by siRNA blocks hSNF5-mediated cellular senescence. Collectively, these results indicate that in human MRT cells, the p16(INK4a)/pRb, rather than the p14(ARF)/p53 pathway, mediates hSNF5-induced cellular senescence.
authors: Gene Regulation Laboratory and Center for Biomedical Genetics, Leiden University Medical Center, The Netherlands.
authors: Igor
authors: I
authors: Oruetxebarria
authors: Francesca
authors: F
authors: Venturini
authors: Tuija
authors: T
authors: Kekarainen
authors: Ada
authors: A
authors: Houweling
authors: Lobke M P
authors: LM
authors: Zuijderduijn
authors: Adone
authors: A
authors: Mohd-Sarip
authors: Robert G J
authors: RG
authors: Vries
authors: Rob C
authors: RC
authors: Hoeben
authors: C Peter
authors: CP
authors: Verrijzer
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone; D019938:Cyclin D1 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D016193:G1 Phase; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D015151:Immunoblotting; D016086:Lentivirus / Q000235:genetics; D009362:Neoplasm Metastasis; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D016160:Retinoblastoma Protein / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000378:metabolism*; D000071796:SMARCB1 Protein; D013997:Time Factors; D014157:Transcription Factors; D015533:Transcriptional Activation; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1