Rb plays a role in survival of Abl-dependent human tumor cells as a downstream effector of Abl tyrosine kinase

Abstract

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.

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

“…Although the mechanism by which BCR-Abl drives leukemiagenesis is well understood, there is little information on the effects of Abl proteins on the development or progression of solid tumors (Singer et al, 2004;Van Diest et al, 2004;Nahta et al, 2005;Nagano et al, 2006;Noren et al, 2006;Vantaggiato et al, 2006). Here, we identify a novel mechanism by which c-Abl promotes breast cancer cell growth and invasion by upregulating ERa expression (Figure 6).…”

Posttranslational Modifications of the Retinoblastoma Tumor Suppressor Protein as Determinants of Function

“…[130][131][132] In G 0 -G 1 cells, Abl is negatively regulated by pRB where binding inhibits Abl activity by masking the kinase domain. 125,126 Nagano et al 133 observed constitutive tyrosine phosphorylation on Y805 of pRB in chronic myelogenous tumor (CML) cells expressing a constitutively active Bcr/Abl fusion protein. From a functional aspect, phosphorylation of Y805 by Abl in these cells plays a role in cell survival.…”

“…This argument is further supported by observations that apoptosis is induced in CML cells upon knockdown of endogenous pRB. 133 It is puzzling that binding of Abl to pRB blocks Abl kinase activity, and yet in Abl dependent CML cells, pRB is constitutively phosphorylated by Abl. Indeed, Nagano et al 133 observed virtually no phosphotyrosine immunoreactivity in pRB/Abl co-immunoprecipitates from CML cells upon overexpression of pRB, indicating a lack of Abl kinase activity.…”

The expression level of the tumor suppressor retinoblastoma protein (Rb) influences the antileukemic efficacy of erucylphospho-N,N,N-trimethylpropylammonium (ErPC3)

“…13,14 Rb also plays a key role in the processes of differentiation 13,15,16 and apoptosis. 13,15,[17][18][19] The activity of Rb is regulated by phosphorylation with the phosphorylated form being inactive and the dephosphorylated form active, i.e., only the dephosphorylated and hypophosphorylated forms of Rb bind to E2F transcription factors and block them from activating the transcription of genes crucial for DNA replication and mitosis. 13 The pathways controlling the activity of Rb start from membrane proteins.…”