TY - JOUR
T1 - Mechanisms of Action of TGF-beta in Cancer Evidence for Smad3 as a Repressor of the hTERT Gene
AU - Li, He
AU - Liu, Jun-Ping
PY - 2007
Y1 - 2007
N2 - Transforming growth factor-beta (TGF-beta) induces cell differentiation and suppresses cell proliferation, but the mechanisms underlying the actions of TGF-beta remain to be fully elucidated. Recent studies suggest that TGF-beta suppresses neoplastic cell development by employing Smad3 protein to repress the gene of human telomerase reverse transcriptase (hTERT). In human breast cancer cells, TGF-beta induces rapid phosphorylation and subsequent entry of Smad3 into the nucleus. In the nucleus, Smad3 binds to the hTERT gene promoter directly and inhibits hTERT gene transcription activity. By interacting with c-myc, Smad3 also represses the c-myc gene. Thus, TGF-beta prevents continuous cell proliferation by switching off telomerase activity through Smad3 repression of the hTERT gene and the action of c-myc. Modulating the interface between Smad3 and the hTERT gene, and the potential feedback loop from telomeres to Smad3 via Smurf2, may represent a novel approach to regulate cell lifespan of proliferation.
AB - Transforming growth factor-beta (TGF-beta) induces cell differentiation and suppresses cell proliferation, but the mechanisms underlying the actions of TGF-beta remain to be fully elucidated. Recent studies suggest that TGF-beta suppresses neoplastic cell development by employing Smad3 protein to repress the gene of human telomerase reverse transcriptase (hTERT). In human breast cancer cells, TGF-beta induces rapid phosphorylation and subsequent entry of Smad3 into the nucleus. In the nucleus, Smad3 binds to the hTERT gene promoter directly and inhibits hTERT gene transcription activity. By interacting with c-myc, Smad3 also represses the c-myc gene. Thus, TGF-beta prevents continuous cell proliferation by switching off telomerase activity through Smad3 repression of the hTERT gene and the action of c-myc. Modulating the interface between Smad3 and the hTERT gene, and the potential feedback loop from telomeres to Smad3 via Smurf2, may represent a novel approach to regulate cell lifespan of proliferation.
UR - http://onlinelibrary.wiley.com/doi/10.1196/annals.1396.016/abstract;jsessionid=DB3ADA342DA7CC9895D19AFFC2F5A49B.d03t03
U2 - 10.1196/annals.1396.016
DO - 10.1196/annals.1396.016
M3 - Article
VL - 1114
SP - 56
EP - 68
JO - Annals of the New York Academy of Sciences
JF - Annals of the New York Academy of Sciences
SN - 0077-8923
ER -