A truncated form of p23 down-regulates telomerase activity via disruption of Hsp90 function.
The Hsp90-associated protein p23 modulates Hsp90 activity during the final stages of the chaperone pathway to facilitate maturation of client proteins. Previous reports indicate that p23 cleavage induced by caspases during cell death triggers destabilization of client proteins. However, the specific role of truncated p23 (Delta p23) in this process and the underlying mechanisms remain to be determined. One such client protein, hTERT, is a telomerase catalytic subunit regulated by several chaperone proteins, including Hsp90 and p23. In the present study, we examined the effects of p23 cleavage on hTERT stability and telomerase activity. Our data showed that overexpression of Delta p23 resulted in a decrease in hTERT levels, and a down-regulation in telomerase activity. Serine phosphorylation of Hsp90 was significantly reduced in cells expressing high levels of Delta p23 compared with those expressing full-length p23. Mutation analyses revealed that two serine residues (Ser-231 and Ser-263) in Hsp90 are important for activation of telomerase, and down-regulation of telomerase activity by Delta p23 was associated with inhibition of cell growth and sensitization of cells to cisplatin. Our data aid in determining the mechanism underlying the regulation of telomerase activity by the chaperone complex during caspase-dependent cell death.
Woo
Sang Hyeok
SH
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Nowon-gu, Seoul 139-706, Korea.
An
Sungkwan
S
Lee
Hyung-Chahn
HC
Jin
Hyeon-Ok
HO
Seo
Sung-Keum
SK
Yoo
Doo-Hyun
DH
Lee
Kee-Ho
KH
Rhee
Chang Hun
CH
Choi
Eui-Ju
EJ
Hong
Seok-Il
SI
Park
In-Chul
IC
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D055550:Protein Stability; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; C073446:protein p23; D019098:Telomerase