p27^kip1 acts as a downstream effector of and is coexpressed with the β_1C integrin in prostatic adenocarcinoma

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Abstract

Integrins are a large family of transmembrane receptors that, in addition to mediating cell adhesion, modulate cell proliferation. The β1C integrin is an alternatively spliced variant of the β1 subfamily that contains a unique 48–amino acid sequence in its cytoplasmic domain. We have shown previously that in vitro β1C inhibits cell proliferation and that in vivo β1C is expressed in nonproliferative, differentiated epithelium and is selectively downregulated in prostatic adenocarcinoma. Here we show, by immunohistochemistry and immunoblotting analysis, that β1C is coexpressed in human prostate epithelial cells with the cell-cycle inhibitor p27kip1, the loss of which correlates with poor prognosis in prostate cancer. In the 37 specimens analyzed, β1C and p27kip1 are concurrently expressed in 93% of benign and 84%–91% of tumor prostate cells. Forced expression of β1Cin vitro is accompanied by an increase in p27kip1 levels, by inhibition of cyclin A–dependent kinase activity, and by increased association of p27kip1 with cyclin A. β1C inhibitory effect on cell proliferation is completely prevented by p27kip1 antisense, but not mismatch oligonucleotides. β1C expression does not affect either cyclin A or E levels, or cyclin E–associated kinase activity, nor the mitogen-activated protein (MAP) kinase pathway. These findings show a unique mechanism of cell growth inhibition by integrins and point to β1C as an upstream regulator of p27kip1 expression and, therefore, a potential target for tumor suppression in prostate cancer.

Authors

Mara Fornaro, Giovanni Tallini, Duo-Qi Zheng, W. Michael Flanagan, Michela Manzotti, Lucia R. Languino