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通过蛋白激酶A介导的磷酸化作用对E2F1活性的调控。

Regulation of E2F1 activity via PKA-mediated phosphorylations.

作者信息

Ertosun Mustafa Gökhan, DİlmaÇ Sayra, Hapİl Fatma Zehra, TanriÖver Gamze, KÖksoy Sadi, ÖzeŞ Osman Nidai

机构信息

Department of Plastic, Reconstructive, and Aesthetic Surgery, Faculty of Medicine, Akdeniz University, Antalya Turkey.

Department of Histology and Embriology, Faculty of Medicine, Akdeniz University, Antalya Turkey.

出版信息

Turk J Biol. 2020 Oct 13;44(5):215-229. doi: 10.3906/biy-2003-9. eCollection 2020.

DOI:10.3906/biy-2003-9
PMID:33110360
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7585165/
Abstract

E2F1 becomes activated during the G1 phase of the cell cycle, and posttranslational modifications modulate its activity. Activation of G-protein coupled receptors (GPCR) by many ligands induces the activation of adenylate cyclases and the production of cAMP, which activates the PKA enzyme. Activated PKA elicits its biological effect by phosphorylating the target proteins containing serine or threonine amino acids in the RxxS/T motif. Since PKA activation negatively regulates cell proliferation, we thought that activated PKA would negatively affect the activity of E2F1. In line with this, when we analyzed the amino acid sequence of E2F1, we found 3 hypothetical consensus PKA phosphorylation sites located at 127-130, 232-235, and 361-364 positions and RYET, RLLS, and RMGS sequences. After showing the binding and phosphorylation of E2F1 by PKA, we converted the codons of Threonine-130, Serine-235, and Serine-364 to Alanine and Glutamic acid codons on the eukaryotic E2F1 expression vector we had previously created. We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence.

摘要

E2F1在细胞周期的G1期被激活，翻译后修饰可调节其活性。许多配体激活G蛋白偶联受体（GPCR）会诱导腺苷酸环化酶激活并产生cAMP，进而激活PKA酶。激活的PKA通过磷酸化RxxS/T基序中含丝氨酸或苏氨酸氨基酸的靶蛋白来发挥其生物学效应。由于PKA激活会对细胞增殖产生负调节作用，我们认为激活的PKA会对E2F1的活性产生负面影响。与此相符的是，当我们分析E2F1的氨基酸序列时，发现3个假定的PKA磷酸化共有位点，分别位于第127 - 130、232 - 235和361 - 364位，序列分别为RYET、RLLS和RMGS。在证实PKA与E2F1结合并使其磷酸化后，我们将真核E2F1表达载体上苏氨酸-130、丝氨酸-235和丝氨酸-364的密码子转换为丙氨酸和谷氨酸密码子。我们通过开发针对这些位点磷酸化特异性形式的单克隆抗体，证实了T130、S235和S364的磷酸化，并表明它们的磷酸化是细胞周期依赖性的。根据我们的结果，PKA介导的E2F1磷酸化会抑制增殖和葡萄糖摄取，并诱导caspase-3激活和细胞衰老。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/32718d40e6e1/turkjbio-44-215-fig008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/aa70c31f5f39/turkjbio-44-215-fig001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/7913fb4d6578/turkjbio-44-215-fig002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/6631a37a7dfc/turkjbio-44-215-fig003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/f2dc894a1e90/turkjbio-44-215-fig004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/eec9a7af3245/turkjbio-44-215-fig005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/8ff3279ab311/turkjbio-44-215-fig006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/f61b115ec609/turkjbio-44-215-fig007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/32718d40e6e1/turkjbio-44-215-fig008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/aa70c31f5f39/turkjbio-44-215-fig001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/7913fb4d6578/turkjbio-44-215-fig002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/6631a37a7dfc/turkjbio-44-215-fig003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/f2dc894a1e90/turkjbio-44-215-fig004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/eec9a7af3245/turkjbio-44-215-fig005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/8ff3279ab311/turkjbio-44-215-fig006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/f61b115ec609/turkjbio-44-215-fig007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b415/7585165/32718d40e6e1/turkjbio-44-215-fig008.jpg

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