Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1.
Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1.
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DOI：
10.1158/0008-5472.can-08-0578
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Gelmann EP
中科院分区：
文献类型：
--
作者：
Markowski MC;Bowen C;Gelmann EP
前列腺炎症是前列腺癌发展的危险因素。在老化的前列腺中，炎性萎缩的区域是前列腺上皮细胞转化的病灶。抑制蛋白NKX3.1的表达在炎性萎缩区域和浸润前前列腺癌中减少。炎性细胞因子TNF-α和IL-1β通过诱导快速泛素化和蛋白酶体降解加速NKX3.1蛋白丢失。TNF-α的作用是通过NKX3.1的C-末端结构域介导的，其中丝氨酸196的磷酸化对于精氨酸诱导的降解至关重要。丝氨酸196突变为丙氨酸消除了该位点的磷酸化以及TNF-α对NKX3.1泛素化和蛋白质丢失的影响。这与由丝氨酸185介导的稳态NKX3.1周转的控制相反。丝氨酸185突变为丙氨酸通过抑制泛素化和使蛋白质半衰期加倍来增加NKX3.1稳态周转。第三个C-末端丝氨酸在位置195上对稳态蛋白质周转和TNF-α诱导的泛素化具有调节作用。因此，NKX3.1肿瘤抑制因子的细胞水平受到靶向C-末端丝氨酸残基以激活泛素化和蛋白质降解的炎性细胞因子的影响。我们的数据表明，抑制炎症或抑制效应激酶的策略可能是预防前列腺癌的有用方法。
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 TNF-α and IL-1β accelerate NKX3.1 protein loss by inducing rapid ubiquitination and proteasomal degradation. The effect of TNF-α is mediated via the C-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-α 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 steady-state turnover by inhibiting ubiquitination and doubling the protein half-life. A third C-terminal serine at position 195 has a modulating effect on both steady state protein turnover and on ubiquitination induced by TNF-α. Thus, cellular levels of the NKX3.1 tumour suppressor are affected by inflammatory cytokines that target C-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.