Reduction of apoptosis in Rb-deficient embryos via Abl knockout

Abstract

The retinoblastoma protein RB regulates cell proliferation, differentiation and apoptosis. Homozygous knockout of Rb in mice causes embryonic lethality owing to placental defects that result in excessive apoptosis. RB binds to a number of cellular proteins including the nuclear Abl protein and inhibits its tyrosine kinase activity. Ex vivo experiments have shown that genotoxic or inflammatory stress can activate Abl kinase to stimulate apoptosis. Employing the Rb-null embryos as an in vivo model of apoptosis, we have shown that the genetic ablation of Abl can reduce apoptosis in the developing central nervous system and the embryonic liver. These results are consistent with the inhibitory interaction between RB and Abl, and provide in vivo evidence for the proapoptotic function of Abl.

Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy

“…31 TUNEL assay was performed as described by Borges and co-workers. 47 Ki-67 antibody used was purchased from BD Pharmingen, San Diego, CA, USA. All cell nuclei were stained with 4′,6-Diamidino-2-phenylindole (DAPI, blue).…”

DNA damage-induced cell death: lessons from the central nervous system

“…Several organs have been employed as in vivo models of IR-induced apoptosis: the gastro-intestinal (GI) tract, the thymus, the developing liver and the developing CNS [47][48][49][50]. Among those, the developing CNS has so far been the most investigated, and thus the focus of this discussion.…”

Reduced Expression of the Retinoblastoma Protein Shows That the Related Signaling Pathway Is Essential for Mediating the Antineoplastic Activity of Erufosine

“…In the context of Rb-deficiency, reduced levels of c-Abl and activation of various apoptotic factors were observed. The C-terminal domain of the Rb protein binds to the kinase domain of c-Abl and inhibits its pro-apoptotic catalytic activity [22], [24], [26], [28], indicating a negative feedback loop between reduced Rb-levels and c-Abl expression. It has been demonstrated that Rb-knockout embryos exhibited inappropriate cell cycle entry and massive apoptosis in nervous system, lens, liver and muscles [64].…”

“…It has been demonstrated that Rb-knockout embryos exhibited inappropriate cell cycle entry and massive apoptosis in nervous system, lens, liver and muscles [64]. According to Borges et al, in Rb-null mice embryos, the knockout of either one or two abl alleles can reduce CNS and liver apoptosis in early embryos suggesting that in Rb −/− genetic background, the pro-apoptotic activity of c-Abl may be enhanced due to the loss of Rb control of the nuclear Abl kinase activity [24]. Other studies have demonstrated that cultured thymocytes derived from rb −/−/ abl −/− embryos showed a reduced apoptotic response to TNF-α [23] and to ionizing radiation in ex vivo cultures [24].…”

“…The activation of c-Abl after DNA damage and p53 activation requires Rb phosphorylation or degradation [22], [26], [27]. Welch and Wang have shown that the C-terminal region of Rb can bind to the Abl tyrosine kinase, leading to the inhibition of its kinase activity [24], [28].…”