| Abstract: |
We report that knocking down the expression of inositol polyphosphate 4-phosphatase type II (INPP4B) in human epithelial cells, like knockdown of PTEN, resulted in enhanced Akt activation and anchorage-independent growth and enhanced overall motility. In xenograft experiments, overexpression of INPP4B resulted in reduced tumor growth. INPP4B preferentially hydrolyzes phosphatidylinositol-3,4-bisphosphate (PI(3,4)P<sub>2</sub>) with no effect on phosphatidylinositol-3.4.5-triphosphate (PI(3,4,5)P<sub>3</sub>), suggesting that PI(3,4)P<sub>2</sub> and PI(3,4,5)P<sub>3</sub> may cooperate in Akt activation and cell transformation. Dual knockdown of INPP4B and PTEN resulted in cellular senescence. Finally, we found loss of heterozygosity (LOH) at the INPP4B locus in a majority of basal-like breast cancers, as well as in a significant fraction of ovarian cancers, which correlated with lower overall patient survival, suggesting that INPP4B is a tumor suppressor. © 2009 Elsevier Inc. All rights reserved. |
| Keywords: |
signal transduction; protein kinase b; cancer survival; controlled study; human tissue; unclassified drug; human cell; overall survival; nonhuman; cell proliferation; ovarian neoplasms; mouse; animal tissue; cells, cultured; gene overexpression; ovary cancer; breast cancer; phosphatase; animal experiment; animal model; enzyme activation; tumor xenograft; breast neoplasms; phosphatidylinositol 3 kinase; cancer inhibition; tumor suppressor gene; cell transformation; tumor suppressor proteins; substrate specificity; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; pten phosphohydrolase; cell movement; epithelium cell; insulin; cellcycle; heterozygosity loss; loss of heterozygosity; breast carcinogenesis; intraductal carcinoma; inositol polyphosphate 4 phosphatase type ii; phosphatidylinositol 3,4 bisphosphate; phosphatidylinositol 3,4,5 trisphosphate; anchorage independent growth; cell aging; cell invasion; cell motility; hydrolysis; phosphoric monoester hydrolases
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