Telomerase activity is critical for normal and transformed human cells to e
scape from crisis and is implicated in oncogenesis. Here we describe a nove
l Pin2/TRF1 binding protein, PinX1 that inhibits telomerase activity and af
fects tumorigenicity. PinX1 and its small TID domain bind the telomerase ca
talytic subunit hTERT and potently inhibit its activity. Overexpression of
PinX1 or its TID domain inhibits telomerase activity, shortens telomeres, a
nd induces crisis:, whereas depletion of endogenous PinX1 increases telomer
ase activity and elongates telomeres. Depletion of PinX1 also increases tum
origenicity in nude mice, consistent with its chromosome localization at 8p
23, a region with frequent loss of heterozygosity in a number of human canc
ers. Thus, PinX1 is a potent telomerase inhibitor and a putative tumor supp
ressor.