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.
Highlights
Protein-tyrosine kinases can be classified into two groups: receptor-type tyrosine kinases and non-receptor-type tyrosine kinases. c-Src, a non-receptor type protein tyrosine kinase, plays a role in a variety of cellular process, including cytoskeletal reorganization, migration, and proliferation [1]
V-Src is an oncogene that was first identified from the Rous sarcoma virus [2]. v-Src is a mutant variant of the cellular proto-oncogene c-Src, due to the loss of the tyrosine residue typically found in c-Src at the C-terminus; v-Src can escape from Csk and is highly activated without binding to the ligands, contributing to the oncogenic character of v-Src
These results suggest that caffeine inhibits v-Src-induced chromosome bridge formation without inhibiting ATR kinase
Summary
Protein-tyrosine kinases can be classified into two groups: receptor-type tyrosine kinases and non-receptor-type tyrosine kinases. c-Src, a non-receptor type protein tyrosine kinase, plays a role in a variety of cellular process, including cytoskeletal reorganization, migration, and proliferation [1]. C-Src, a non-receptor type protein tyrosine kinase, plays a role in a variety of cellular process, including cytoskeletal reorganization, migration, and proliferation [1]. The activity of c-Src is regulated by Csk-catalyzed phosphorylation of the C-terminal tyrosine residue. This phosphorylation generates intramolecular binding between the SH2 domain and the phosphorylated tyrosine residue, resulting in the formation of closed conformation and inhibition of the kinase activity. V-Src is a mutant variant of the cellular proto-oncogene c-Src, due to the loss of the tyrosine residue typically found in c-Src at the C-terminus; v-Src can escape from Csk and is highly activated without binding to the ligands, contributing to the oncogenic character of v-Src. Upon v-Src expression, cells lose actinInts. Tfahielurreef-oinred,uwceed pmrouplotisneuctlheaattiovn-S. rcT-hinerdeufocreed, cwheromproospoomsee tbhraitdges are ovn-Serco-fintdhuecceaduscehsroomf tohseomv-eSrcb-riinddguescedaremaolnigenaonf t tphreogcraeussseiosnooff cthaencevr-Screcl-lisn.duced malignant progression of cancer cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
