INI1 expression induces cell cycle arrest and markers of senescence in malignant rhabdoid tumor cells.
The INI1 gene, which encodes a functionally uncharacterized protein component of the hSWI/SNF chromatin remodeling complex, is often mutated or deleted in malignant rhabdoid tumor (MRT). Two isoforms of INI1, that differ by the variable inclusion of nine amino acids, potentially are produced by differential RNA splicing. To determine the effect of the two INI1 isoforms on cell growth, INI1-devoid (MRT) and INI1-expressing cell lines were transfected separately with mammalian expression vectors or transduced with adenoviruses. Transfection of the short form of INI1 into either INI1-deficient or expressing cell lines resulted in complete suppression of cell growth in colony formation assays. The longer splice variant induced moderate to severe growth suppression of MRT cells, but had a far milder effect on non-MRT cells. Transduction of MRT cells with adenoviruses expressing either isoform of INI1 led to a dramatic change in morphology, growth suppression, and cell cycle arrest. Furthermore, senescence-associated proteins were up-regulated after transduction, while levels of proteins implicated in cell cycle progression were down-regulated. Adenoviral delivery of INI1 into a non-MRT cell line, however, had no demonstrable effect on any of these parameters. These results support the genetic evidence that INI1 is a tumor suppressor gene gone awry in MRT cells, and also suggest that delivery of the INI1 gene to MRT cells by adenoviruses may lead to a more effective treatment of this highly aggressive malignancy.
Reincke
Britta S
BS
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Rosson
Gary B
GB
Oswald
Betty W
BW
Wright
Cynthia F
CF
D000256:Adenoviridae / Q000235:genetics; D015415:Biomarkers; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology; D018335:Rhabdoid Tumor / Q000235:genetics*; D000071796:SMARCB1 Protein; D014157:Transcription Factors; D014410:Tumor Stem Cell Assay
D015415:Biomarkers; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors