TGF-beta and cancer: is Smad3 a repressor of hTERT gene?
Transforming growth factor beta (TGF-beta) carries out tumor suppressor activity in epithelial and lymphoid cells, whereas telomerase is required for most cancers. Although the molecular mechanisms by which TGF-beta acts as a tumor suppressor are yet to be fully established, a link between TGFb and its tumor suppressor activity by telomerase has been suggested. Recently, we have noted a novel mode of action for TGF-beta through which human telomerase reverse transcriptase (hTERT) gene is repressed in immortal and neoplastic cells, confirming that one of the mechanisms underlying TGF-beta suppression of tumor growth may be through inhibiting hTERT gene transcription. Moreover, the inhibition of hTERT gene by TGF-beta suggests a cis action of the TGF-beta signaling molecule Smad3 on hTERT promoter directly. This article examines our current understanding and investigation of TGF-beta regulation of telomerase activity, and presents a model in which Smad3 participates in regulating hTERT gene transcription by acting as a repressor directly. Engineering the interface between Smad3 and hTERT gene may lead to a new strategy to inhibit telomerase activity in cancer.
Li
He
H
Department of Immunology, Molecular Signaling Laboratory, Monash University, Melbourne, Australia. he.li@med.monash.edu.au
Xu
Dakang
D
Toh
Ban-Hock
BH
Liu
Jun-Ping
JP
D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D012097:Repressor Proteins; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D019098:Telomerase