title: The nuclear import of oncoprotein hepatitis B X-interacting protein depends on interacting with c-Fos and phosphorylation of both proteins in breast cancer cells.
abstract: Aberrant nuclear localization of oncogenic transcription factors and coactivators always leads to the development of cancer. We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) acts as a novel transcriptional coactivator to promote proliferation and migration of breast cancer cells. However, the mechanism of regulating the nuclear import of HBXIP remains unclear. In the present study, we found that HBXIP interacted with c-Fos through their leucine zipper domains in vitro and in vivo. Interestingly, the leucine zipper mutant of HBXIP (or c-Fos) was unavailable to bind to c-Fos (or HBXIP), resulting in the disappearance of nuclear localization of HBXIP. Moreover, we revealed that the nuclear import of HBXIP was required for phosphorylation of c-Fos at Thr(232), Thr(325), Thr(331), and Ser(374) by ERK1/2. In addition, the mutant of HBXIP at the Ser(108) phosphorylation site failed to import into the nucleus. Strikingly, we found that the kinase ataxia telangiectasia mutated (ATM) phosphorylated HBXIP at Ser(108). The knockdown of ATM by siRNA remarkably decreased the levels of serine phosphorylation and blocked the nuclear import of HBXIP. Then, we identified that ATM could bind to HBXIP. Moreover, we validated that the nuclear import of HBXIP contributed to its nuclear function. Therefore, we conclude that the nuclear import of the oncoprotein HBXIP requires interaction with c-Fos through their leucine zipper domains and phosphorylation of both proteins in breast cancer cells. Thus, our findings provide new insights into the mechanism of the nuclear import of HBXIP. Therapeutically, the block of the nuclear import of HBXIP is significant in breast cancer.
authors.affiliation: Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hang
authors.initials: H
authors.lastname: Li
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cai
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.forename: Leilei
authors.initials: L
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Lihong
authors.initials: L
authors.lastname: Ye
mesh_terms: D021581:Active Transport, Cell Nucleus; D020816:Amino Acid Motifs; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D018613:Microscopy, Confocal; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D013844:Thiazoles; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D012694:Serine; C022616:thiazolyl blue
keywords: ATM; Breast Cancer; Coactivator Transcription; HBXIP; Nuclear Import; Nuclear Transport; Oncogene; Phosphorylation; c-Fos