title: EGFR/MDM2 signaling promotes NF-κB activation via PPARγ degradation.
abstract: Dysregulated expression of epidermal growth factor receptor (EGFR) has been implicated in many cancer events, while peroxisome proliferator-activated receptor γ (PPARγ) negatively regulates cancer progression. The molecular mechanism of EGFR interaction with PPARγ is still unclear. Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase. PPARγ degradation by EGFR/MDM2 signaling resulted in accumulation of nuclear factor-kappaB (NF-κB)/p65 protein levels and increasing NF-κB activation. In contrast, PPARγ-Y74A mutant reversed this event. Moreover, PPARγ-Y74A mutant suppressed cell proliferation and increased chemotherapeutic agent-induced cancer cell sensitivity. Importantly, the clinical findings show that the nuclear phosphorylation of PPARγ-Y74 and EGFR expression in colonic cancer tissues was higher than that in control normal tissues. Thus, our study revealed a novel molecular mechanism that nuclear EGFR/NF-κB signaling promoted cell proliferation by destructing PPARγ function, which provides a novel strategy for cancer treatment.
authors.affiliation: Department of Oncology, The Affiliated Wujin Hospital, Jiangsu University, Changzhou, Jiangsu 213037, People's Republic of China.|Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China.|Department of Central Laboratory and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Oncology, The Affiliated Wujin Hospital, Jiangsu University , Changzhou, Jiangsu 213037 , People's Republic of China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Jin
authors.affiliation: Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China.|Department of General Surgery, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, Jiangsu 212002, People's Republic of China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Institute of Life Science, Jiangsu University , Zhenjiang, Jiangsu 212013 , People's Republic of China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Life Science, Jiangsu University , Zhenjiang, Jiangsu 212013 , People's Republic of China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Oncology, The Affiliated Wujin Hospital, Jiangsu University , Changzhou, Jiangsu 213037 , People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Jiangsu Taizhou People's Hospital , Jiangsu 225309 , People's Republic of China.
authors.forename: Chenglin
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Oncology, The Affiliated Wujin Hospital, Jiangsu University , Changzhou, Jiangsu 213037 , People's Republic of China.
authors.forename: Qinggang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Oncology, The Affiliated Wujin Hospital, Jiangsu University , Changzhou, Jiangsu 213037 , People's Republic of China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Oncology, The Affiliated Wujin Hospital, Jiangsu University, Changzhou, Jiangsu 213037, People's Republic of China.|Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu 212013, People's Republic of China.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Institute of Life Science, Jiangsu University , Zhenjiang, Jiangsu 212013 , People's Republic of China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Shi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016328:NF-kappa B; D047495:PPAR gamma; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C512478:EGFR protein, human; D066246:ErbB Receptors