DDB2 is involved in ubiquitination and degradation of PAQR3 and regulates tumorigenesis of gastric cancer cells

Qiao, Shushan; Guo, Weiwei; Liao, Lujian; Wang, Lin; Wang, Zheng; Zhang, Rui; Xu, Daqian; Zhang, Yuxue; Pan, Yi; Wang, Zhenzhen; Chen, Yan

doi:10.1042/bj20150253

Cited by 24 publications

(32 citation statements)

References 40 publications

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“…RT-qPCR analysis demonstrated that PAQR3 mRNA expression was significantly lower in ESCC tissues compared with in PCHNT tissues, which was consistent with the data in other cancer types, including breast cancer ( 11 ), colon cancer ( 15 ) and gastric cancer ( 13 ), demonstrating that PAQR3 may be an ESCC suppressor gene. The tumor suppressive function of PAQR3 is primarily achieved by inhibiting activation of the ERK signaling pathway ( 9 ).…”

Section: Discussionsupporting

confidence: 85%

“…These knockout mice had significantly increased proliferation of epidermal keratinocytes, and PAQR3 gene deletion promoted the development and progression of dimethylbutylamine/12-O-tetradecanoyl-phorbol-12-acetate-induced skin cancer. Other studies have reported downregulated expression of PAQR3 in liver ( 10 ), gastric ( 13 , 14 ), colon ( 15 ) and breast cancer ( 11 ), and determined that this downregulation was associated with tumor progression, metastasis and prognosis. However, the role and mechanism underlying the action of PAQR3 in ESCC has not been reported.…”

Section: Introductionmentioning

confidence: 98%

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Suppressor PAQR3 associated with the clinical significance and prognosis in esophageal squamous cell carcinoma

et al. 2018

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Progestin and adipoQ receptor family member 3 (PAQR3) is a novel tumor suppressor; however, its function in esophageal cancer is not well understood. The present study explored the association between PAQR3, and the survival and clinical phenotype in patients with esophageal squamous cell carcinoma (ESCC). The expression of PAQR3 in 80 cases of ESCC and its corresponding adjacent tissues was detected by reverse transcription-quantitative polymerase chain reaction. The results demonstrated that PAQR3 expression in cancer tissues was significantly lower compared with that in adjacent tissues. Clinicopathological analysis indicated that PAQR3 expression was significantly correlated with ethnicity (P=0.032), tumor length (P=0.019), lymph node metastasis (P=0.011) and local recurrence (P=0.009). Notably, the Kaplan-Meier survival curve demonstrated that a decrease in PAQR3 expression was associated with poor prognosis in patients with ESCC. Multivariate analysis indicated that PAQR3 expression was an independent prognostic indicator for patients with ESCC. PAQR3 may serve an important role in the progress of ESCC and become a potential candidate for ESCC targeted therapy.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 98%

Suppressor PAQR3 associated with the clinical significance and prognosis in esophageal squamous cell carcinoma

et al. 2018

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“…An anti-GFP antibody was used to detect GFP-PAQR3 or GFP-PAQR3(NΔ20) (upper panel), and an anti-Hsp90 antibody was used as a gel loading control (lower panel). Consistent with the immunoblot shown, previous results have demonstrated that PAQR3 and PAQR3(NΔ20) display no detectable difference in mobility [24, 62]. C , Shown is a bar graph quantitating the effect of PAQR3, PAQR3(NΔ20), and the effect of Gβγ and PKD inhibitors in the presence of PAQR3 on Golgi fragmentation.…”

Section: Figuresupporting

confidence: 80%

PAQR3 regulates Golgi vesicle fission and transport via the Gβγ–PKD signaling pathway

Hewavitharana

Wedegaertner

2015

Cellular Signalling

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Heterotrimeric G proteins function at diverse subcellular locations, in addition to canonical signaling at the plasma membrane (PM). Gβγ signals at the Golgi, via protein kinase D (PKD), to regulate fission of PM-destined vesicles. However, the mechanism by which Gβγ is regulated at the Golgi in this process remains elusive. Recent studies have revealed that PAQR3 (Progestin and AdipoQ Receptor 3), also called RKTG (Raf Kinase Trapping to the Golgi), interacts with the Gβ subunit and localizes Gβ to the Golgi thereby inhibiting Gβγ signaling at the PM. Herein we show that, in contrast to this inhibition of canonical Gβγ signaling at the PM, PAQR3 promotes Gβγ signaling at the Golgi. Expression of PAQR3 causes fragmentation of the Golgi, while a Gβ binding-deficient mutant of PAQR3 does not cause Golgi fragmentation. Also, a C-terminal fragment of GRK2 (GRK2ct), which interacts with Gβγ and inhibits Gβγ signaling, and gallein, a small molecule inhibitor of Gβγ, are both able to inhibit PAQR3-mediated Golgi fragmentation. Furthermore, a dominant negative form of PKD (PKD-DN) and a pharmacological inhibitor of PKD, Gö6976, also inhibit PAQR3-mediated fragmentation of the Golgi. Importantly, expression of the Gβ binding-deficient mutant of PAQR3 inhibits the constitutive transport of the model cargo protein VSV-G from the Golgi to the PM, indicating the involvement of PAQR3 in Golgi-to PM vesicle transport and a dominant negative role for this mutant. Collectively, these results reveal a novel role for the newly characterized, Golgi-localized PAQR3 in regulating Gβγ at the non-canonical subcellular location of the Golgi and thus for controlling Golgi-to-PM protein transport via the Gβγ-PKD signaling pathway.

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“…Hence, DDB2 also acts as a tumor suppressor. In terms of DDB2 functions in ubiquitination and degradation, a current report revealed that DDB2 could facilitate tumorigenesis of gastric cancer via ubiquitination and degradation of the tumor suppressor progestin and adipoQ receptor family member 3 [22]. Similarly, we also found that DDB2 mediates ubiquitination and degradation of the AR via the CUL4A-DDB1 E3 ligase complex [23].…”

Section: Introductionmentioning

confidence: 85%

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

et al. 2017

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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.

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DDB2 is involved in ubiquitination and degradation of PAQR3 and regulates tumorigenesis of gastric cancer cells

Cited by 24 publications

References 40 publications

Suppressor PAQR3 associated with the clinical significance and prognosis in esophageal squamous cell carcinoma

Suppressor PAQR3 associated with the clinical significance and prognosis in esophageal squamous cell carcinoma

PAQR3 regulates Golgi vesicle fission and transport via the Gβγ–PKD signaling pathway

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

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