Rb plays a role in survival of Abl-dependent human tumor cells as a downstream effector of Abl tyrosine kinase.
The retinoblastoma (Rb) gene product is a tumor suppressor that is mutated or inactivated in many types of human cancers. Although Rb is known to be an upstream negative regulator of Abl protein tyrosine kinase, we propose here that Rb also functions as a downstream effector of Abl that plays a positive role in survival of Abl-dependent human tumor cells, including Bcr/Abl-positive chronic myelogenous leukemia (CML). We show that Rb is constitutively phosphorylated at tyrosine in Abl-dependent tumor cells, and that Abl phosphorylates Rb specifically at Y805 within the C-terminal domain of the molecule. We also show that ectopic expression of Rb induces apoptosis in Abl-dependent tumor cells by inhibiting the Abl tyrosine kinase activity, and that Rb-induced apoptosis is compromised by Abl-catalysed phosphorylation of Rb at Y805. Furthermore, the silencing of endogenous Rb by RNA interference induced apoptosis in Abl-dependent tumor cells. Thus, our findings suggest that Abl-catalysed tyrosine phosphorylation of Rb is necessary for survival of Abl-dependent human tumor cells, and raises the possibility that this phosphorylated Rb can be a molecular target for cancer therapy aimed at inducing apoptosis of Abl-dependent tumor cells, such as Bcr/Abl-positive CML.
Nagano
K
K
Division of Proteomics Research, Institute of Medical Science, University of Tokyo, Minato-ku, Japan.
Itagaki
C
C
Izumi
T
T
Nunomura
K
K
Soda
Y
Y
Tani
K
K
Takahashi
N
N
Takenawa
T
T
Isobe
T
T
D017209:Apoptosis; D002384:Catalysis; D002470:Cell Survival; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000502:physiology*
D016160:Retinoblastoma Protein; D016315:Proto-Oncogene Proteins c-abl