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Inflammatory Cytokines Induce Phosphorylation and Ubiquitination of Prostate Suppressor Protein NKX3.1

¹ Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York and ² Lombardi Comprehensive Cancer Center, Washington, District of Columbia

Requests for reprints: Edward P. Gelmann, Columbia University, Milstein Hospital 6N-435, 177 Fort Washington Avenue, New York, NY 10032. Phone: 212-305-8602; Fax: 212-305-3035; E-mail: gelmanne{at}columbia.edu.

Key Words: NKX3.1 • prostate cancer • ubiquitination

Inflammation of the prostate is a risk factor for the development of prostate cancer. In the aging prostate, regions of inflammatory atrophy are foci for prostate epithelial cell transformation. Expression of the suppressor protein NKX3.1 is reduced in regions of inflammatory atrophy and in preinvasive prostate cancer. Inflammatory cytokines tumor necrosis factor (TNF)- and interleukin-1β accelerate NKX3.1 protein loss by inducing rapid ubiquitination and proteasomal degradation. The effect of TNF- is mediated via the COOH-terminal domain of NKX3.1 where phosphorylation of serine 196 is critical for cytokine-induced degradation. Mutation of serine 196 to alanine abrogates phosphorylation at that site and the effect of TNF- on NKX3.1 ubiquitination and protein loss. This is in contrast to control of steady-state NKX3.1 turnover, which is mediated by serine 185. Mutation of serine 185 to alanine increases NKX3.1 protein stability by inhibiting ubiquitination and doubling the protein half-life. A third COOH-terminal serine at position 195 has a modulating effect on both steady-state protein turnover and on ubiquitination induced by TNF-. Thus, cellular levels of the NKX3.1 tumor suppressor are affected by inflammatory cytokines that target COOH-terminal serine residues to activate ubiquitination and protein degradation. Our data suggest that strategies to inhibit inflammation or to inhibit effector kinases may be useful approaches to prostate cancer prevention. [Cancer Res 2008;68(17):6896–901]