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: Jihoon Ryu, Zeenia Kaul, A-Rum Yoon, Ye Liu, Tomoko Yaguchi, Youjin Na, Hyo Min Ahn, Ran Gao, Il-Kyu Choi, Chae-Ok Yun, Sunil C Kaul, Renu Wadhwa
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 36 Pg. 24832-44 (Sep 05 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25012652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• HSP70 Heat-Shock Proteins
• Heterogeneous-Nuclear Ribonucleoprotein K
• Tumor Suppressor Protein p53
• mortalin
• Telomerase

Topics

• Animals
• Blotting, Western
• Cell Line
• Cell Nucleus (metabolism)
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• HCT116 Cells
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• HeLa Cells
• Heterogeneous-Nuclear Ribonucleoprotein K (metabolism)
• Humans
• Immunohistochemistry
• MCF-7 Cells
• Mice, Inbred BALB C
• Mice, Nude
• Mutation
• Neoplasm Metastasis
• Neoplasms (genetics, metabolism, pathology)
• Oxidative Stress
• Telomerase (genetics, metabolism)
• Transplantation, Heterologous
• Tumor Suppressor Protein p53 (genetics, metabolism)