Myosin VI is differentially regulated by DNA damage in p53- and cell type-dependent manners.

Abstract

Myosin VI is an unconventional motor protein and functions in a variety of intracellular processes such as cell migration, vesicular trafficking, and homeostasis of the Golgi complex. Previously, we found that myosin VI is up-regulated in RKO, LS174T, and H1299 cells by DNA damage in a p53-dependent manner and mediates the pro-survival function of p53. Here, we showed that the levels of myosin VI protein were markedly inhibited in MCF7 and LNCaP cells by topoisomerase I-II inhibitors. However, the levels of myosin VI transcript were decreased only by topoisomerase I inhibitors. We also found that the levels of myosin VI protein were markedly inhibited in MCF7 cells by wild-type p53 but not tumor-derived mutant p53. Surprisingly, we found that the level of myosin VI transcript was slightly increased instead of decreased in MCF7 cells by p53, suggesting that a mechanism other than transcriptional repression is involved. Additionally, we found that on the myosin VI promoter, the level of acetylated histone H3 was markedly decreased, whereas that of p53 and acetylated histone H4 was slightly increased in MCF7 cells upon treatment with topoisomerase I-II inhibitors. Finally, we showed that overexpression of myosin VI enhances, whereas knockdown of myosin VI decreases, DNA damage-induced stabilization of p53, and consequently, knockdown of myosin VI de-sensitizes MCF7 cells to DNA damage-induced apoptosis. Taken together, as a mediator of the p53 pro-survival pathway and a marker of malignancy in some tumors, differential regulation of myosin VI in various tumor cells by topoisomerase inhibitors dictates whether knockdown of myosin VI inhibits, rather than enhances, the susceptibility of tumor cells to some therapeutic agents, which might be explored for designing a proper therapeutic strategy.

• Authors: Seong Jun Cho, Xinbin Chen
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 35 Pg. 27159-27166 (Aug 27 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20576604 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Enzyme Inhibitors
• Histones
• RNA, Messenger
• TP53 protein, human
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Tumor Suppressor Protein p53
• myosin VI
• Myosin Heavy Chains
• DNA Topoisomerases, Type I
• DNA Topoisomerases, Type II

Topics

• Apoptosis
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• DNA Damage
• DNA Topoisomerases, Type I (metabolism)
• DNA Topoisomerases, Type II (metabolism)
• Enzyme Inhibitors (pharmacology)
• Histones (genetics, metabolism)
• Humans
• Mutation
• Myosin Heavy Chains (genetics, metabolism)
• Neoplasms (drug therapy, genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Transcription, Genetic
• Tumor Suppressor Protein p53 (genetics, metabolism)