title: PCTAIRE1 phosphorylates p27 and regulates mitosis in cancer cells.
abstract: PCTAIRE1 is distant relative of the cyclin-dependent kinase family that has been implicated in spermatogenesis and neuronal development, but it has not been studied in cancer. Here, we report that PCTAIRE1 is expressed in prostate, breast, and cervical cancer cells, where its RNAi-mediated silencing causes growth inhibition with aberrant mitosis due to defects in centrosome dynamics. PCTAIRE1 was not similarly involved in proliferation of nontransformed cells, including diploid human IMR-90 fibroblasts. Through yeast two-hybrid screening, we identified tumor suppressor p27 as a PCTAIRE1 interactor. In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells. In a mouse xenograft model of PPC1 prostate cancer, conditional silencing of PCTAIRE1 restored p27 protein expression and suppressed tumor growth. Mechanistic studies in HeLa cells showed that PCTAIRE1 phosphorylates p27 during the S and M phases of the cell cycle. Notably, p27 silencing was sufficient to rescue cells from mitotic arrest caused by PCTAIRE1 silencing. Clinically, PCTAIRE1 was highly expressed in primary breast and prostate tumors compared with adjacent normal epithelial tissues. Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Teruki
authors.initials: T
authors.lastname: Yanagi
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California. smatsuzawa@sanfordburnham.org reedoffice@sanfordburnham.org.
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Matsuzawa
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California. smatsuzawa@sanfordburnham.org reedoffice@sanfordburnham.org.
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008938:Mitosis; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; C089463:PCTAIRE-1 protein kinase