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The role of PinX1 in the regulation of telomerase and oncogenesis
Author(s) -
Soohoo Christina Y,
Miron Alexander,
Iglehart James D,
Lu Kun Ping,
Zhou Xiao Zhen
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a984-a
Subject(s) - telomerase , telomere , carcinogenesis , telomerase reverse transcriptase , biology , microbiology and biotechnology , cancer research , cancer , gene , genetics
Telomerase activity is critical for normal and transformed human cells to escape from crisis and is implicated in oncogenesis. Our lab has previously identified the novel telomerase inhibitor PinX1. PinX1 inhibits telomerase activity and telomere elongation by binding to the catalytic subunit of telomerase, hTert, with its C‐terminal telomerase inhibitory domain (TID). Consequently, depletion of endogenous PinX1 in cells increases telomerase activity and tumorigenicity in nude mice, whereas overexpression of PinX1 or its TID forces cancer cells into growth crisis and eventually senescence, suggesting that PinX1 is a putative tumor suppressor. To elucidate the mechanism of telomerase inhibition by PinX1 and its significance in tumorigenesis, we have generated a series of truncation, and single and multiple amino acid substitutions in PinX1 as well as identified a number of genetic alterations in the PINX1 gene in human cancer tissues and cell lines. These mutant proteins were expressed and purified to examine how they affect the ability of PinX1 to bind to and inhibit telomerase. We have found that several mutant proteins are severely impaired in their ability to bind to and inhibit telomerase activity. The results have identified amino acid sequences that are important for PinX1 to regulate telomerase and that may also be involved in cell transformation. Research is supported by Dept. of Defense Breast Cancer Research Program Predoctoral Traineeship Award BC043758 to C.Y.S. and NIH grants CA022082 to K.P.L. and GM56230 to X.Z.Z.