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hcinap negatively regulates NF-κB signaling by recruiting the phosphatase PP1 to deactivate IKK complex

Journal of Molecular Cell Biology 2015年第6期7卷 529-542页

作者： Linglong Qu Yapeng Ji Xi Zhu Xiaofeng Zheng State Key Lab of Protein and Plant Gene Research Beijing 100871China Department of Biochemistry and Molecular Biology School of Life SciencesPeking UniversityBeijing 100871China Department of Critical Care Medicine Peking University Third HospitalBeijing 100191China

Tight regulation of nuclear factor-kB(NF-kB)signaling is essential to maintain homeostasis in immune system in response to various stimuli,which hasbeen studied extensivelyand ***,the molecularmechanisms responsible for its negative regulation are not completely *** we demonstrate that human coilin-interacting nuclear ATPase protein(hcinap)is a novel negative regulator in NF-kB signaling by deactivating IkB kinase(IKK)*** response to TNF stimulation,hcinap dynamically associates with IKKa and IKKb and inhibits IKK ***,hcinap directly interacts with the catalytic subunits of protein phosphatase 1(PP1)and mediates the formation of IKK–hcinap–PP1 complex,serving as an adaptor protein that recruits PP1 to dephosphorylate ***,decreased levels of hcinap are observed in several inflammatory diseases with NF-kB *** study suggests a novel mechanism underlying deactivation of IKK and provides new insight into the negative regulation of NF-kB signaling.

关键词： hcinap NF-κB IKK complex phosphatase PP1 inflammatory diseases

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hcinap alleviates senescence by regulating MDM2 via p14ARF and the HDAC1/CoREST complex

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Journal of Molecular Cell Biology 2023年第2期15卷 58-71页

作者： Xinping Huang Yan Zhao Min Wei Ruipeng Zhuge Xiaofeng Zheng State Key Laboratory of Protein and Plant Gene Research School of Life SciencesPeking UniversityBeĳing 100871China Department of Biochemistry and Molecular Biology School of Life SciencesPeking UniversityBeĳing 100871China

Cellular senescence is a major process affected by multiple signals and coordinated by a complex signal response *** of novel regulators of cellular senescence and elucidation of their molecular mechanisms will aid in the discoveryof new treatment strategies for aging-related diseases. In the present study, we identified human coilin-interacting nuclear ATPaseprotein (hcinap) as a negative regulator of aging. Depletion of cCINAP significantly shortened the lifespan of Caenorhabditiselegans and accelerated primary cell aging. Moreover, mCINAP deletion markedly promoted organismal aging and stimulatedsenescence-associated secretory phenotype in the skeletal muscle and liver from mouse models of radiation-induced ***, hcinap functions through regulating MDM2 status by distinct mechanisms. On the one hand, hcinap decreasesp53 stability by attenuating the interaction between p14ARF and MDM2;on the other hand, hcinap promotes MDM2 transcriptionvia inhibiting the deacetylation of H3K9ac in the MDM2 promoter by hindering the HDAC1/CoREST complex integrity. Collectively,our data demonstrate that hcinap is a negative regulator of aging and provide insight into the molecular mechanisms underlyingthe aging process.

关键词： hcinap HDAC1/CoREST complex p14ARF MDM2 transcription senescence

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hcinap regulates the DNA damage response and mediates the resistance of acute myelocytic leukemia cells to therapy

hCINAP regulates the DNA damage response and mediates the re...

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中国生物化学与分子生物学会2019年全国学术会议暨学会成立四十周年

作者： Ruidan Xu Xiaofeng Zheng State Key Laboratory of Protein and Plant Gene Research Department of Biochemistry and Molecular Biology School of Life Sciences Peking University

Maintenance of genomic stability is critical for the proper function of organisms. When DNA damage occurs and is detected, a series of repair proteins sequentially accumulate at the damaged site and induce signal transduction pathways to initiate the subsequent repair of double-stranded DNA breaks(DSB). Acute myeloid leukemia(AML) is a genetically heterogeneous malignant disorder of the hematopoietic system, characterized by the accumulation of DNA-damaged immature myeloid precursors. In this study, we find that hcinap is involved in the repair of DSB and that its expression correlates with AML prognosis. hcinap is a highly conserved adenylate kinase that plays essential roles in the growth of eukaryotic cells. Following DSB, hcinap is recruited to damage sites where it promotes SENP3-dependent deSUMOylation of NPM1, which in turn results in the dissociation of RAP80 from the damage site and CTIP-dependent DNA resection and homologous recombination. NPM1 SUMOylation is required for recruitment of DNA repair proteins at the early stage of DSB, and SUMOylated NPM1 impacts the assembly of the BRCA1 complex. Moreover, we find that knockdown of hcinap also sensitizes a patient-derived xenograft(PDX) mouse model to chemotherapy. In clinical AML samples, low hcinap expression is associated with a higher overall survival rate in patients. These results provide mechanistic insight into the function of hcinap during the DNA damage response and its role in AML resistance to therapy. Meanwhile, the discovery of sumoylation/desumoylation pathways that function to control DNA damage repair highlights the possibility of modulating these PTM activities in order to protect healthy cells from the effects of genotoxic anticancer therapies, while still eliminating the cancer cells. As the analogous ubiquitination system can easily be targeted by drugs, such pleiotropic mechanisms can be of substantial use in cancer treatments, offering a number of possibilities for future applications.

关键词： hcinap NPM1 double-stranded DNA breaks(DSB) SUMOylation acute myeloid leukemia(AML)

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hcinap在宫颈癌细胞放射抵抗中的作用研究

hCINAP在宫颈癌细胞放射抵抗中的作用研究

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作者：覃念群广西医科大学

学位级别：硕士

目的和意义:宫颈癌是女性患者最常见恶性肿瘤,其发病率和死亡率占据第四,主要发生在发展中国家。放射治疗是宫颈癌的治疗手段之一,在各期宫颈癌治疗中发挥重要作用,但部分患者会因出现放射抵抗而导致治疗失败。因此阐明宫颈癌放射抵抗... 详细信息

目的和意义:宫颈癌是女性患者最常见恶性肿瘤,其发病率和死亡率占据第四,主要发生在发展中国家。放射治疗是宫颈癌的治疗手段之一,在各期宫颈癌治疗中发挥重要作用,但部分患者会因出现放射抵抗而导致治疗失败。因此阐明宫颈癌放射抵抗的分子机制是提高疗效、改善预后的关键所在。人类螺旋蛋白相关反应核ATP酶蛋白(hcinap),也称腺苷酸激酶6,是一种具有腺苷酸激酶域的蛋白。hcinap可通过介导糖酵解酶LDHA的磷酸化增加Warburg效应,促进肿瘤细胞的增殖、侵袭、自我更新及化疗抵抗。在缺氧条件下,hcinap促进宫颈癌细胞的迁移和侵袭能力。但是hcinap是否参与调控宫颈癌放射抵抗尚不清楚,因此需要进一步研究。方法:(1)临床收集患者的宫颈癌组织及癌旁正常组织,Western blot检测hcinap在宫颈癌中的表达水平,HPA数据库进行验证;构建稳定转染的敲低和过表达hcinap的宫颈癌细胞,通过Western blot验证hcinap的表达效果;CCK8实验、划痕实验和Transwell实验观察敲低/过表达hcinap对宫颈癌细胞增殖、迁移和侵袭能力的影响。(2)给予不同剂量射线处理宫颈癌细胞,Western blot和RT-PCR检测宫颈癌细胞中hcinap表达,联合射线处理,通过CCK8实验、细胞死亡实验和细胞克隆形成实验观察敲低和过表达hcinap对宫颈癌细胞放射抵抗的影响,Western blot观察γ-H2AX的表达水平;敲低和过表达hcinap后,联合射线照射处理宫颈癌细胞,Western blot观察AKT/mTOR信号通路的关键蛋白表达情况,给予AKT/mTOR信号通路抑制剂Torin1联合射线处理后,Western blot观察AKT/mTOR信号通路的关键蛋白表达情况;CCK8实验和细胞死亡实验检测hcinap是否通过AKT/mTOR信号通路影响宫颈癌放射抵抗。结果:(1)在收集到宫颈癌组织及癌旁正常宫颈组织中,与癌旁正常宫颈组织相比,hcinap蛋白在宫颈癌组织中表达升高(P=0.03),HPA数据库进行验证;敲低hcinap可降低宫颈癌细胞的增殖、迁移和侵袭能力,反之,过表达hcinap可促进宫颈癌细胞增殖、迁移和侵袭。(2)射线可诱导宫颈癌细胞中hcinap表达上调;敲低hcinap并联合射线处理后,与阴性对照组(sh-NC)相比,宫颈癌细胞的增殖能力减弱,细胞死亡率增加,细胞克隆形成数显著减少,γ-H2AX蛋白表达明显增加。(3)过表达hcinap并联合射线处理后,与空载组(vector)相比,宫颈癌细胞的增殖能力较高,细胞死亡率减少,细胞克隆形成数显著增加,γ-H2AX蛋白表达明显减少。(4)敲低hcinap并联合射线处理后,与阴性对照组(sh-NC)相比,hcinap敲低组(sh-hcinap)细胞中的p-AKT和p-mTOR蛋白表达水平降低,反之,过表达hcinap后,宫颈癌细胞中p-AKT和p-mTOR蛋白表达被逆转,给予AKT/mTOR通路抑制剂Torin1联合射线照射处理后,hcinap过表达组(OE-hcinap)组细胞中p-AKT和p-mTOR表达水平显著降低、增殖能力下降、细胞死亡率增加、细胞克隆形成数减少。结论:(1)hcinap在宫颈癌组织中高表达,敲低hcinap则可减少宫颈癌细胞增殖、迁移和侵袭,过表达hcinap则相反。(2)射线照射后可诱导宫颈癌细胞中hcinap表达上调。(3)敲低hcinap降低宫颈癌细胞放射抵抗并促进DNA损伤。(4)过表达hcinap增强宫颈癌细胞放射抵抗并减少DNA损伤。(5)过表达hcinap通过激活AKT/mTOR信号通路增强宫颈癌细胞放射抵抗。

关键词：宫颈癌 hcinap 放射抵抗 AKT/mTOR信号通路

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