Authors: Wadhwa R; Ryu J; Gao R; Choi IK; Morrow G; Kaur K; Kim I; Kaul SC; Yun CO; Tanguay RM
Abstract: Aging is a complex process accompanied by a decreased capacity of cells to cope with random damages induced by reactive oxygen species, the natural by-products of energy metabolism, leading to protein aggregation in various components of the cell. Chaperones are important players in the aging process as they prevent protein misfolding and aggregation. Small chaperones, such as small heat shock proteins, are involved in the refolding and/or disposal of protein aggregates, a feature of many age-associated diseases. In Drosophila melanogaster, mitochondrial Hsp22 (DmHsp22), is localized in the mitochondrial matrix and is preferentially up-regulated during aging. Its overexpression results in an extension of life span (>30%) (Morrow, G., Samson, M., Michaud, S., and Tanguay, R. M. (2004) FASEB J. 18, 598-599 and Morrow, G., Battistini, S., Zhang, P., and Tanguay, R. M. (2004) J. Biol. Chem. 279, 43382-43385). Long lived flies expressing Hsp22 also have an increased resistance to oxidative stress and maintain locomotor activity longer. In the present study, the cross-species effects of Hsp22 expression were tested. DmHsp22 was found to be functionally active in human cells. It extended the life span of normal fibroblasts, slowing the aging process as evidenced by a lower level of the senescence associated beta-galactosidase. DmHsp22 expression in human cancer cells increased their malignant properties including anchorage-independent growth, tumor formation in nude mice, and resistance to a variety of anticancer drugs. We report that the DmHsp22 interacts and inactivates wild type tumor suppressor protein p53, which may be one possible way of its functioning in human cells.
Keywords: Animals; Antineoplastic Agents/pharmacology; Blotting, Western; Cell Aging/drug effects/genetics/physiology; Cell Line; Cell Line, Tumor; *Cell Proliferation; Cell Survival/drug effects; Drosophila Proteins/genetics/metabolism/*physiology; Drug Resistance, Neoplasm/genetics; Etoposide/pharmacology; Female; Fibroblasts/cytology/drug effects/metabolism; Heat-Shock Proteins/genetics/metabolism/*physiology; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondrial Proteins/genetics/metabolism/*physiology; Neoplasms, Experimental/genetics/metabolism/pathology; Nocodazole/pharmacology; Paclitaxel/pharmacology; Transfection; Transplantation, Heterologous; Tumor Suppressor Protein p53/metabolism|
Journal: The Journal of biological chemistry Volume: 285 Issue: 6 Pages: 3833-9 Date: Dec. 2, 2009 PMID: 19948727 |
Wadhwa R, Ryu J, Gao R, Choi IK, Morrow G, Kaur K, Kim I, Kaul SC, Yun CO, Tanguay RM (2010) Proproliferative functions of Drosophila small mitochondrial heat shock protein 22 in human cells. The Journal of biological chemistry 285: 3833-9.
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