title: DDB2 is involved in ubiquitination and degradation of PAQR3 and regulates tumorigenesis of gastric cancer cells.
abstract: DDB2 (damage-specific DNA-binding protein 2) is the product of the xeroderma pigmentosum group E gene which is involved in the initiation of nucleotide excision repair via an ubiquitin ligase complex together with DDB1 and CUL4A (cullin 4A). PAQR3 (progestin and adipoQ receptor family member III) is a newly discovered tumour suppressor that is implicated in the development of many types of human cancers. In the present paper, we report that DDB2 is involved in ubiquitination and degradation of PAQR3. DDB2 is able to interact with PAQR3 in vivo and in vitro. Both overexpression and knockdown experiments reveal that the protein expression level, protein stability and polyubiquitination of PAQR3 are changed by DDB2. Negative regulation of EGF (epidermal growth factor)- and insulin-induced signalling by PAQR3 is also altered by DDB2. At the molecular level, Lys(61) of PAQR3 is targeted by DDB2 for ubiquitination. The cell proliferation rate and migration of gastric cancer cells are inhibited by DDB2 knockdown and such effects are abrogated by PAQR3 knockdown, indicating that the effect of DDB2 on the cancer cells is mediated by PAQR3. Collectively, our studies not only pinpoint that DDB2 is a post-translational regulator of PAQR3, but also indicate that DDB2 may play an active role in tumorigenesis via regulating PAQR3.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Qiao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Daqian
authors.initials: D
authors.lastname: Xu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yuxue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China ychen3@sibs.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054875:Ubiquitination
chemical_list: C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C532354:PAQR3 protein, human
keywords: DDB2; cell proliferation; gastric cancer; protein degradation; tumour suppressor; ubiquitination