NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer

Abstract

Both nuclear receptor interaction protein (NRIP) and DNA damage binding protein 2 (DDB2) belong to the Cullin 4 (CUL4)-DDB1 binding protein family and are androgen receptor (AR)-interacting proteins. Here, we investigated the expression patterns of the NRIP, DDB2 and AR proteins in human prostate cancer tissues and found that the expression levels of NRIP and AR were higher, but the DDB2 level was lower, in prostate cancer tissues than in non-neoplastic controls, suggesting NRIP as a candidate tumor promoter and DDB2 as a tumor suppressor in prostate cancer. Furthermore, both NRIP and DDB2 shared the same AR binding domain; they were competitors for the AR, but not for DDB1 binding, in the AR-DDB2-DDB1-CUL4A complex. Conclusively, NRIP stabilizes the AR protein by displacing DDB2 from the AR-DDB2 complex. Consistent with our hypothesis, a specific expression pattern with high levels of NRIP and AR, together with a low level of DDB2, was found more frequently in the human prostate cancer tissues with a cribriform pattern than in non-cribriform tumors, suggesting that disruption of the balance between NRIP and DDB2 may change AR protein homeostasis and contribute to pathogenesis in certain aggressive types of prostate cancer.

Muscle‐restricted nuclear receptor interaction protein knockout causes motor neuron degeneration through down‐regulation of myogenin at the neuromuscular junction

“…Nuclear receptor interaction protein might participate in various cellular functions, including regulating muscle contraction, promoting cell growth, and inhibiting protein degradation . Here, we provide a novel function of NRIP and a novel muscle‐derived neuronal supporting factor indicating that muscular NRIP expression is essential for spinal motor neuron support.…”

“…However, genetic variations in the NRIP genome location are associated with cardiovascular disease, osteoporosis, and schizophrenia . Nuclear receptor interaction protein is also named DCAF6 and belongs to Cul4‐DDB1 associated factors . Mutation at R317C of DCAF8 responding to DDB1 binding was identified as the genetic cause of axonal hereditary motor and sensory neuropathy .…”

“…[6][7][8] Nuclear receptor interaction protein is also named DCAF6 and belongs to Cul4-DDB1 associated factors. 9,10 Mutation at R317C of DCAF8 responding to DDB1 binding was identified as the genetic cause of axonal hereditary motor and sensory neuropathy. 11 Thus, NRIP might also play a role in neuropsychological diseases.…”

DDB2 Regulates DNA Replication through PCNA-Independent Degradation of CDT2

“…In this study, we reported that CRL4 DDB2 is a new E3 ubiquitin ligase targeting CDT2 for its proteolysis. DNA damage binding protein 2 (DDB2), another substrate receptor for CRL4 E3 ubiquitin ligase [18][19][20][21][22], is originally identi ed as damage-speci c DNA binding protein, and involves in the early step of DNA damage recognition of nucleotide excision repair (NER), which is induced by UV radiation [23][24][25][26][27]. Recently, increasing evidences suggest that DDB2 plays an important role in suppressing tumorigenesis [19,[28][29][30][31][32].…”

“…Recently, increasing evidences suggest that DDB2 plays an important role in suppressing tumorigenesis [19,[28][29][30][31][32]. DDB2 is low expressed in skin cancer, breast cancer, colon cancer, prostate cancer, and ovarian cancer [18,29,30,[33][34][35]. DDB2-de cient mice have the high rate to develop malignant tumors compared to their XP-de cient littermates [36].…”