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A Novel Mechanism for Chaperone-mediated Telomerase Regulation during Prostate Cancer Progression¹

Departments of Pathology [A. A., L. W. E. H. L. F., B. A. A., E. D. M., J. L. W., S. E. H.], and Human Genetics [J. L. W., S. E. H.], Massey Cancer Center, Medical College of Virginia at Virginia Commonwealth University, Richmond, Virginia 23298, and Department of Human Biology/Program in Genomics, The Fred Hutchison Cancer Center, Seattle Washington 98109 [P. S. N.]

Telomerase activity has been detected in >85% of all malignant human cancers, including 90% of prostate carcinomas. Using a well-characterized experimental prostate cancer system, we have found that telomerase activity is notably increased (>10-fold) during tumorigenic conversion. Expression profiles of the telomerase components (hTR and hTERT) revealed no substantive changes, which suggests a nontranscriptional mechanism for increased activity. Because the hsp90 chaperone complex functionally associates with telomerase, we investigated that relationship and found that along with telomerase activity, a number of hsp90-related chaperones are markedly elevated during transformation, as well as in advanced prostate carcinomas. Using the nontumorigenic cell protein extract as the source of telomerase, addition of purified chaperone components enhanced reconstitution of telomerase activity, which suggests a novel mechanism of increased telomerase assembly via a hsp90 chaperoning process during prostate cancer progression.

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