RB-resistant Abl kinase induces delayed cell cycle progression and increases susceptibility to apoptosis upon cellular stresses through interaction with p53.
c-Abl, a non-receptor tyrosine kinase, is found in both nucleus and cytoplasm of proliferating fibroblasts. RB negatively regulates the kinase activity of c-Abl. Overexpression of kinase active c-Abl can overcome RB-induced growth arrest in Saos-2 cells. However, we previously reported that disruption of the RB matchmaker function leads to delayed cell cycle progression in the presence of p53. In this study, we investigated whether overexpression of mutant c-Abl (AS2, RB-resistant Abl kinase) not only lead to delayed cell cycle progression but also make cells susceptible to apoptosis under coexpression with a fragment of RB C pocket in human skin fibroblast. AS2 expressing cells showed delayed cell growth rate in normal growth condition. After genotoxic stress such as etoposide treatment, AS2 expressing cells readily progressed into apoptosis through p53 and caspase-3 activations. Our results suggest that expression of AS2 not only induces delayed cell cycle progression but also results in increased sensitivity to apoptosis in the presence of p53.
Cho
Jae-We
JW
Department of Microbiology, College of Medicine, Seonam University, Chunpook 590-711, Republic of Korea.
Chung
Junah
J
Baek
Won-Ki
WK
Suh
Seong-Il
SI
Kwon
Taeg Kyu
TK
Park
Jong-Wook
JW
Suh
Min-Ho
MH
D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D016213:Cyclins / Q000235:genetics; D017931:DNA Primers; D005047:Etoposide / Q000633:toxicity; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D016213:Cyclins; D017931:DNA Primers; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases