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The Fer kinas: a novel target for prostate cancer<br />
intervention<br />
Uri Nir, Orel Pasder, Sally Shpungin, Yaniv Salem, Shlomit Vilchick,<br />
Shulamit Michaeli and Hana Malovani<br />
Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel<br />
Fer is a nuclear and cytoplasmic tyrosine kinase whose levels are increased in prostate<br />
tumors. Herein we show that Fer is required for malignant cell-cycle progression<br />
in-vitro and for tumor progression in-vivo. Decreasing the level of Fer using the<br />
RNA interference (RNAi) approach, impeded the proliferation of prostate carcinoma<br />
cells and led to their arrest at the G0/G1 phase. At the molecular level, knock-down<br />
of Fer resulted in a profound hypo-phosphorylation of the retinoblastoma protein<br />
(pRB) on both CDK4 and CDK2 phosphorylation sites. De-phosphorylation of pRB<br />
was not seen upon the direct targeting of either CDK4 or CDK2 expression, and<br />
was only partially achieved by the simultaneous depletion of these two kinases.<br />
Amino acids sequence analysis revealed two protein phosphatase 1 (PP1) binding<br />
motifs in the kinase domain of Fer and the association of Fer with PP1α in-vivo was<br />
verified using co-immunoprecipitation analysis. Down-regulation of Fer potentiated<br />
the de-phosphorylation of pRB by PP1α and over-expression of Fer decreased the<br />
phosphatase activity of PP1α. Hence, Fer is a novel regulator of cell-cycle progression<br />
in prostate carcinoma cells and this portrays it as a potential target for prostate<br />
cancer intervention.<br />
l35<br />
53<br />
Thus, knock-down of Fer subverts redundant G1-S promoting activities and induces<br />
cell-cycle arrest in malignant cells. Our findings portray Fer as a novel intervening<br />
target for cancer therapy.
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