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J. Biol. Chem., Vol. 279, Issue 3, 1692-1702, January 16, 2004

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Regulation of _1C and _1A Integrin Expression in Prostate Carcinoma Cells^*

Loredana Moro, Elda Perlino, Ersilia Marra, Lucia R. Languino¶, and Margherita Greco

From the Institute of Biomembranes and Bioenergetics, National Research Council (C.N.R.), 70126 Bari, Italy and the ^¶Department of Cancer Biology and Cancer Center, University of Massachusetts, School of Medicine, Worcester, Massachusetts 01605

_1C and _1A integrins are two splice variants of the human ₁ integrin subfamily that act as an inhibitor and a stimulator of cell proliferation, respectively. In neoplastic prostate epithelium, both these variants are down-regulated at the mRNA level, but only _1C protein levels are reduced. We used an experimental model consisting of PNT1A, a normal immortalized prostate cell line, and LNCaP and PC-3, two prostate carcinoma cell lines, to investigate both the transcription/post-transcription and translation/post-translation processes of _1C and _1A. Transcriptional regulation played the key role for the reduction in _1C and _1A mRNA expression in cancer cells, as _1C and _1A mRNA half-lives were comparable in normal and cancer cells. _1C translation rate decreased in cancer cells in agreement with the decrease in mRNA levels, whereas _1A translation rate increased more than 2-fold, despite the reduction in mRNA levels. Both _1C and _1A proteins were degraded more rapidly in cancer than in normal cells, and pulse-chase experiments showed that intermediates and/or rates of _1C and _1A protein maturation differ in cancer versus normal cells. Inhibition of either calpain- or lysosomal-mediated proteolysis increased both _1C and _1A protein levels, the former in normal but not in cancer cells and the latter in both cell types, albeit at a higher extent in cancer than in normal cells. Interestingly, inhibition of the ubiquitin proteolytic pathway increased expression of ubiquitinated _1C protein without affecting _1A protein levels in cancer cells. These results show that transcriptional, translational, and post-translational processes, the last involving the ubiquitin proteolytic pathway, contribute to the selective loss of _1C integrin, a very efficient inhibitor of cell proliferation, in prostate malignant transformation.

Received for publication, July 21, 2003 , and in revised form, October 20, 2003.

^* This work was supported by the MURST-PPRST Cluster 03 grant (to E. M.), by the ARMY, Prostate Cancer Research Program Grant DAMD17-98-1-8506 (to L. R. L.), and by a grant from the Associazione Italiana Ricerca sul Cancro (AIRC) (to E. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Institute of Biomembranes and Bioenergetics, National Research Council (C.N.R.), Via Amendola 165/A, 70126 Bari, Italy. Tel.: 39-080-544-2412; Fax: 39-080-544-3317; E-mail: csmmlm22{at}area.ba.cnr.it.

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