title: HBXIP, a binding protein of HBx, regulates maintenance of the G2/M phase checkpoint induced by DNA damage and enhances sensitivity to doxorubicin-induced cytotoxicity.
abstract: To maintain the integrity of the genome, cells need to detect and repair DNA damage before they complete cell division. Hepatitis B x-interacting protein (HBXIP), a binding protein of HBx (Hepatitis B virus × protein), is aberrantly overexpressed in human cancer cells and show to promote cell proliferation and inhibit apoptosis. The present study is designed to investigate the role of HBXIP on the DNA damage response. Our results show that HBXIP acts as an important regulator of G2/M checkpoint in response to DNA damage. HBXIP knockdown increases phospho-histone H2AX expression and foci formation after treatment with ionizing radiation (IR). HBXIP regulates the ATM-Chk2 pathway following DNA damage. Depletion of HBXIP abrogates IR-induced G2/M cell cycle checkpoints, accompanying decrease the expression of phospho-Cdc25C, phospho-Cdc2 (Tyr15) and p27. We also show that downregulation of HBXIP expression sensitizes cancer cells to chemotherapy, as evidenced by an increase in apoptosis and cleavage of caspase-3 and caspase-9. Our data suggest that HBXIP can function as a mediator protein for DNA damage response signals to activate the G2/M checkpoint to maintain genome integrity and prevent cell death.
authors.affiliation: a School of Pharmacology, Taishan Medical University , Taian , P.R. China.
authors.forename: Hongrong
authors.initials: H
authors.lastname: Fei
authors.affiliation: b Department of Radiation Oncology , Central Hospital of Taian , Taian , P.R. China.
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: c School of Life Sciences, Taishan Medical University , Chang Cheng Road, Taian , P.R. China.
authors.forename: Ruotong
authors.initials: R
authors.lastname: Li
authors.affiliation: d Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University , Taian , P.R. China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Yang
authors.affiliation: a School of Pharmacology, Taishan Medical University , Taian , P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: c School of Life Sciences, Taishan Medical University , Chang Cheng Road, Taian , P.R. China.|d Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University , Taian , P.R. China.
authors.forename: Fengze
authors.initials: F
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000528:radiation effects; D020868:Gene Silencing / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000528:radiation effects; D011485:Protein Binding / Q000187:drug effects / Q000528:radiation effects; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D014965:X-Rays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C110719:LAMTOR5 protein, human; D034741:RNA, Small Interfering; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D004317:Doxorubicin; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human
keywords: ATM-Chk2; DNA damage; G2/M phase; HBXIP; chemosensitivity