v-Src Causes Chromosome Bridges in a Caffeine-Sensitive Manner by Generating DNA DamageReportar como inadecuado

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Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan


Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan


Author to whom correspondence should be addressed.

Academic Editor: Guillermo T. Sáez

Abstract An increase in Src activity is commonly observed in epithelial cancers. Aberrant activation of the kinase activity is associated with malignant progression. However, the mechanisms that underlie the Src-induced malignant progression of cancer are not completely understood. We show here that v-Src, an oncogene that was first identified from a Rous sarcoma virus and a mutant variant of c-Src, leads to an increase in the number of anaphase and telophase cells having chromosome bridges. v-Src increases the number of γH2AX foci, and this increase is inhibited by treatment with PP2, a Src kinase inhibitor. v-Src induces the phosphorylation of KAP1 at Ser824, Chk2 at Thr68, and Chk1 at Ser345, suggesting the activation of the ATM-ATR pathway. Caffeine decreases the number of cells having chromosome bridges at a concentration incapable of inhibiting Chk1 phosphorylation at Ser345. These results suggest that v-Src induces chromosome bridges via generation of DNA damage and the subsequent DNA damage response, possibly by homologous recombination. A chromosome bridge gives rise to the accumulation of DNA damage directly through chromosome breakage and indirectly through cytokinesis failure-induced multinucleation. We propose that v-Src-induced chromosome bridge formation is one of the causes of the v-Src-induced malignant progression of cancer cells. View Full-Text

Keywords: v-Src; chromosome bridge; DNA damage; caffeine v-Src; chromosome bridge; DNA damage; caffeine

Autor: Masayoshi Ikeuchi 1, Yasunori Fukumoto 2, Takuya Honda 2, Takahisa Kuga 1, Youhei Saito 1, Naoto Yamaguchi 2 and Yuji Nakayama 1,*

Fuente: http://mdpi.com/


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