Protein phosphatase 2A inhibits nuclear telomerase activity in human breast cancer cells.
Most cancer cells have increased levels of telomerase activity implicated in cell immortalization. Activation of telomerase, a ribonucleoprotein complex, catalyzes the elongation of the ends of mammalian chromosomal DNA (telomeres), the length of which regulates cell proliferation. Currently, how telomerase is regulated in cancer is not yet established. The present study shows that telomerase activity is regulated by protein phosphorylation in human breast cancer cells. Incubation of cell nuclear telomerase extracts with protein phosphatase 2A (PP2A) abolished the telomerase activity; in contrast cytoplasmic telomerase activity was unaffected, and protein phosphatases 1 and 2B were ineffective. Inhibition of telomerase activity by PP2A was both concentration- and time-dependent and was prevented by the protein phosphatase inhibitor okadaic acid. In addition, nuclear telomerase inhibited by PP2A was reactivated by endogenous protein kinase(s) in the presence of ATP, but not in the presence of ATPgammaS. Furthermore, telomerase activity in cultured human breast cancer PMC42 cells was stimulated by okadaic acid, consistent with a role for PP2A in the regulation of telomerase activity in intact cells. These findings suggest that protein phosphorylation reversibly regulates the function of telomerase and that PP2A is a telomerase inhibitory factor in the nucleus of human breast cancer cells.
Li
H
H
Baker Medical Research Institute, Commercial Road, Prahran, Victoria 3181, Australia.
Zhao
L L
LL
Funder
J W
JW
Liu
J P
JP
D001943:Breast Neoplasms / Q000201:enzymology*; D002467:Cell Nucleus / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D054648:Protein Phosphatase 2; D019098:Telomerase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D019319:Okadaic Acid; D011494:Protein Kinases; D019098:Telomerase; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2