Identification and Functional Characterization of Nuclear Mortalin in Human Carcinogenesis [Molecular Bases of Disease]

July 10th, 2014 by Ryu, J., Kaul, Z., Yoon, A.-R., Liu, Y., Yaguchi, T., Na, Y., Ahn, H. M., Gao, R., Choi, I.-K., Yun, C.-O., Kaul, S. C., Wadhwa, R.

Hsp70 family protein, mortalin, an essential chaperone that is frequently enriched in cancer cells and exists in various subcellular sites including mitochondria, plasma membrane, endoplasmic reticulum (ER) and cytosol. Although, molecular mechanisms underlying its multiple subcellular localizations are not yet clear, their functional significance has been revealed by several studies. In the present 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 mortalin mutant that lacked mitochondrial targeting signal peptide and found it to be largely localized in the nucleus and hence called nuclear mortalin (mot-N). Functional characterization of mot-N revealed that it efficiently protects cancer cells against endogenous and exogenous oxidative stress. Furthermore, as compared to 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 (i) inactivation of tumor suppressor protein p53 functions and (ii) interaction and functional activation of telomerase and heterogeneous ribonucleoprotein-K (hnRNP-K) proteins.