title: Up-regulation of survivin during immortalization of human myofibroblasts is linked to repression of tumor suppressor p16(INK4a) protein and confers resistance to oxidative stress.
abstract: Survivin is an essential component of the chromosomal passenger complex and a member of the inhibitor of apoptosis family. It is expressed at high levels in a large variety of malignancies, where it has been implicated in drug resistance. It was also shown previously that survivin is up-regulated during telomerase-mediated immortalization, which occurs at a relatively early stage during carcinogenesis. This study shows that up-regulation of survivin during immortalization of human myofibroblasts is an indirect consequence of the repression of p16(INK4a). Survivin and p16(INK4a) were functionally linked by assays that showed that either the up-regulation of survivin or repression of p16(INK4a) rendered telomerase-transduced MRC-5 myofibroblasts resistant to oxidative stress. Conversely, siRNA-mediated down-regulation of survivin activated caspases and enhanced the sensitivity of immortal MRC-5 cells to oxidative stress. The E2F1 transcription factor, which is negatively regulated by the pRB/p16(INK4a) tumor suppressor pathway, was implicated in the up-regulation of survivin. Using the ChIP assay, it was shown that E2F1 directly interacted with the survivin gene (BIRC5) promoter in cells that spontaneously silenced p16(INK4a) during telomerase-mediated immortalization. E2F1 binding to the BIRC5 was also enhanced in telomerase-transduced cells subjected to shRNA-mediated repression of p16(INK4a). Together, these data show that repression of p16(INK4a) contributes to the up-regulation of survivin and thereby provides a survival advantage to cells exposed to oxidative stress during immortalization. The up-regulation of survivin during immortalization likely contributes to the vulnerability of immortal cells to transformation by oncogenes that alter intracellular redox state.
authors: Cancer Cell Development Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales 2031, Australia.
authors: Chin-Yi
authors: CY
authors: Kan
authors: Carlotta
authors: C
authors: Petti
authors: Lauryn
authors: L
authors: Bracken
authors: Michelle
authors: M
authors: Maritz
authors: Ning
authors: N
authors: Xu
authors: Rosemary
authors: R
authors: O'Brien
authors: Chen
authors: C
authors: Yang
authors: Tao
authors: T
authors: Liu
authors: Jun
authors: J
authors: Yuan
authors: Richard B
authors: RB
authors: Lock
authors: Karen L
authors: KL
authors: MacKenzie
mesh_terms: D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000235:genetics; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020218:Response Elements; D000077022:Survivin; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C107489:BIRC5 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D019098:Telomerase