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PMID:18757402

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Citation

Markowski, MC, Bowen, C and Gelmann, EP (2008) Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1. Cancer Res. 68:6896-901

Abstract

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)-alpha and interleukin-1beta accelerate NKX3.1 protein loss by inducing rapid ubiquitination and proteasomal degradation. The effect of TNF-alpha 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-alpha 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-alpha. 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.

Links

PubMed PMC2586101 Online version:10.1158/0008-5472.CAN-08-0578

Keywords

Alanine/genetics; Cell Line, Tumor; Cytokines/physiology; Homeodomain Proteins/chemistry; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Humans; Inflammation Mediators/physiology; Male; Mutagenesis, Site-Directed; Phosphorylation; Prostate/metabolism; Serine/genetics; Transcription Factors/chemistry; Transcription Factors/genetics; Transcription Factors/metabolism; Ubiquitin/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NKX31

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0035690: cellular response to drug

ECO:0000270: expression pattern evidence used in manual assertion

P

  • has_input:(CHEBI:52717)

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0035690: cellular response to drug

ECO:0000270: expression pattern evidence used in manual assertion

P

has_input:(CHEBI:52717)

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0071347: cellular response to interleukin-1

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0071356: cellular response to tumor necrosis factor

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NKX31

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

See also

References

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