Survivin enhances telomerase activity via up-regulation of specificity protein 1- and c-Myc-mediated human telomerase reverse transcriptase gene transcription.
Suppression of apoptosis is thought to contribute to carcinogenesis. Survivin, a member of the inhibitor-of-apoptosis family, blocks apoptotic signaling activated by various cellular stresses. Since elevated expression of survivin observed in human cancers of varied origin was associated with poor patient survival, survivin has attracted growing attention as a potential target for cancer treatment. Immortalization of cells also is required for carcinogenesis; telomere length maintenance by telomerase is required for cancer cells to proliferate indefinitely. Yet how cancer cells activate telomerase remains unclear. We therefore examined possible interrelationships between survivin expression and telomerase activity. Correlation between survivin and human telomerase reverse transcriptase (hTERT) expression was observed in colon cancer tissues, and overexpression of survivin enhanced telomerase activity by up-regulation of hTERT expression in LS180 human colon cancer cells. DNA-binding activities of specificity protein 1 (Sp1) and c-Myc to the hTERT core promoter were increased in survivin gene transfectant cells. Phosphorylation of Sp1 and c-Myc at serine and threonine residues was enhanced by survivin, while total amounts of these proteins were unchanged. Further, "knockdown" of survivin by a small inhibitory RNA decreased Sp1 and c-Myc phosphorylation. Thus survivin participates not only in inhibition of apoptosis, but also in prolonging cellular lifespan.
Endoh
Teruo
T
Department of Clinical Laboratory Medicine, Sapporo Medical University, School of Medicine, South-1, West-16, Sapporo 060-8543, Japan.
Tsuji
Naoki
N
Asanuma
Koichi
K
Yagihashi
Atsuhito
A
Watanabe
Naoki
N
D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D000077022:Survivin; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
C107489:BIRC5 protein, human; D002867:Chromones; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; C489427:MYC protein, human; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D000077022:Survivin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019098:Telomerase