title: Identification and functional characterization of nuclear mortalin in human carcinogenesis.
abstract: The Hsp70 family protein mortalin is an essential chaperone that is frequently enriched in cancer cells and exists in various subcellular sites, including the mitochondrion, plasma membrane, endoplasmic reticulum, and cytosol. Although the molecular mechanisms underlying its multiple subcellular localizations are not yet clear, their functional significance has been revealed by several studies. In this study, we examined the nuclear fractions of human cells and found that the malignantly transformed cells have more mortalin than the normal cells. We then generated a mortalin mutant that lacked a mitochondrial targeting signal peptide. It was largely localized in the nucleus, and, hence, is called nuclear mortalin (mot-N). Functional characterization of mot-N revealed that it efficiently protects cancer cells against endogenous and exogenous oxidative stress. Furthermore, compared with the full-length mortalin overexpressing cancer cells, mot-N derivatives showed increased malignant properties, including higher proliferation rate, colony forming efficacy, motility, and tumor forming capacity both in in vitro and in vivo assays. We demonstrate that mot-N promotes carcinogenesis and cancer cell metastasis by inactivation of tumor suppressor protein p53 functions and by interaction and functional activation of telomerase and heterogeneous ribonucleoprotein K (hnRNP-K) proteins.
authors.affiliation: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine, Tsukuba, Ibaraki 305-8562, Japan, the Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Korea, and.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Ryu
authors.affiliation: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine, Tsukuba, Ibaraki 305-8562, Japan, the Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, Ohio 43210.
authors.forename: Zeenia
authors.initials: Z
authors.lastname: Kaul
authors.affiliation: the Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Korea, and.
authors.forename: A-Rum
authors.initials: AR
authors.lastname: Yoon
authors.affiliation: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine, Tsukuba, Ibaraki 305-8562, Japan.
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine, Tsukuba, Ibaraki 305-8562, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yaguchi
authors.affiliation: the Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Korea, and.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Na
authors.affiliation: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine, Tsukuba, Ibaraki 305-8562, Japan, the Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Korea, and.
authors.forename: Hyo Min
authors.initials: HM
authors.lastname: Ahn
authors.affiliation: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine, Tsukuba, Ibaraki 305-8562, Japan.
authors.forename: Ran
authors.initials: R
authors.lastname: Gao
authors.affiliation: the Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Korea, and.
authors.forename: Il-Kyu
authors.initials: IK
authors.lastname: Choi
authors.affiliation: the Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Korea, and chaeok@hanyang.ac.kr.
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
authors.affiliation: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine, Tsukuba, Ibaraki 305-8562, Japan, s-kaul@aist.go.jp.
authors.forename: Sunil C
authors.initials: SC
authors.lastname: Kaul
authors.affiliation: From the Cell Proliferation Research Group and Department of Biotechnology (DBT, India)-National Institute of Advanced Industrial Science and Technology (AIST, Japan) International Laboratory for Advanced Biomedicine, Tsukuba, Ibaraki 305-8562, Japan, renu-wadhwa@aist.go.jp.
authors.forename: Renu
authors.initials: R
authors.lastname: Wadhwa
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045325:HCT116 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D016159:Tumor Suppressor Protein p53; C080352:mortalin; D019098:Telomerase
keywords: Cancer Biology; Heat Shock Protein (HSP); Mortalin; Nuclear Localization; Telomerase; Telomerase Activation; Tumor Promoter; hnRNP-K; p53; p53 Inactivation