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PPAR? induces cell apoptosis by destructing Bcl2.

ABSTRACT: PPAR? belongs to the peroxisome-proliferator-activated receptors (PPARs) family, which plays a critical role in inhibiting cell proliferation and tumorigenesis, while the molecular mechanism is still unclear. Here we report that PPAR? serves as an E3 ubiquitin ligase to govern Bcl2 protein stability. PPAR? physically bound to Bcl2 protein. In this process, PPAR?/C102 was critical for PPAR? binding to BH3 domain of Bcl2, subsequently, PPAR? transferred K48-linked polyubiquitin to lysine-22 site of Bcl2 resulting in its ubiquitination and proteasome-dependent degradation. Importantly, overexpression of PPAR? enhanced cancer cell chemotherapy sensitivity. In contrast, silenced PPAR? decreased this event. These findings revealed a novel mechanism of PPAR? governed endogenous Bcl2 protein stability leading to reduced cancer cell chemoresistance, which provides a potential drug target for cancer treatment.

SUBMITTER: Gao J

PROVIDER: S-EPMC4792581 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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PPARα induces cell apoptosis by destructing Bcl2.

Gao Jiaming J Liu Qian Q Xu Ying Y Gong Xin X Zhang Runyun R Zhou Chenglin C Su Zhaoliang Z Jin Jianhua J Shi Haifeng H Shi Juanjuan J Hou Yongzhong Y

Oncotarget 20151201 42

PPARα belongs to the peroxisome-proliferator-activated receptors (PPARs) family, which plays a critical role in inhibiting cell proliferation and tumorigenesis, while the molecular mechanism is still unclear. Here we report that PPARα serves as an E3 ubiquitin ligase to govern Bcl2 protein stability. PPARα physically bound to Bcl2 protein. In this process, PPARα/C102 was critical for PPARα binding to BH3 domain of Bcl2, subsequently, PPARα transferred K48-linked polyubiquitin to lysine-22 site o ...[more]

PMID: 26556865

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Project description:Introduction:Curcumin has various biological properties including being anti-inflammatory and antidiabetic. Podocyte apoptosis and autophagy dysfunction have been found to be responsible for the development of diabetic nephropathy (DN). Thus, the aim of the study was to investigate the effects of curcumin on the podocyte apoptosis and autophagy in DN and clarify its potential mechanisms. Methods:The mice with DN induced by injection of streptozotocin were treated with curcumin by gavage at a dose of 200 mg/kg/day for 8 weeks. The serum lipid levels were detected by total cholesterol (TC) and triglyceride (TG) kits at different time points. Renal damage was assessed by detecting urine albumin, serum creatinine (Scr), HE staining and PAS staining. The renal impairment was detected by immunohistochemical staining and TUNEL staining. Western blot assay tested the expression of autophagy-related and apoptotic-related proteins in vivo and vitro. The viabilities and apoptosis of MPC5 cells exposed to high glucose (HG) or curcumin were respectively detected by CCK-8 assay and flow cytometry. Results:The results showed that curcumin significantly decreased the progress of DN possibly via increasing autophagy and inhibiting apoptosis of renal cell in DN mice. Besides, podocyte marker proteins (podocalyxin and nephrin) were markedly increased in DN mice by curcumin treatment. The autophagy-related proteins LC3, p62, Beclin1, UVRAG and ATG5 were significantly affected in DN mice by curcumin, along with reducing expression of pro-apoptotic protein Bax and caspase-3 and increasing anti-apoptotic protein Bcl-2. In vitro, curcumin increased the viabilities and inhibited apoptosis of MPC5 cells exposed to high glucose (HG). In addition, the podocyte autophagy was enhanced partly via regulating beclin1/UVRAG. Discussion:Together, the results showed that curcumin inhibited podocyte apoptosis and accelerated cell autophagy via regulating Beclin1/UVRAG/Bcl2. Thus, the study showed that curcumin exerted significantly protective effects in DN.

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PPAR? induces cell apoptosis by destructing Bcl2.

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PPARα induces cell apoptosis by destructing Bcl2.

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