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New roles for the RB tumor suppressor protein

The Ben May Institute for Cancer Research, The University of Chicago, The Knapp Medical Research Building, BSLC-R118, 924 East 57th Street, Chicago, IL 60637, USA.
Current Opinion in Genetics & Development (Impact Factor: 8.57). 03/2004; 14(1):55-64. DOI: 10.1016/j.gde.2003.11.005
Source: PubMed

ABSTRACT For a gene whose existence was first postulated in 1971, was cloned in 1986 and whose functions have been extensively characterized ever since, you might be inclined to think there was not much new to report regarding the retinoblastoma tumor suppressor gene (RB)--but you would be wrong to make such an assumption. RB is still piquing our interest with several activities defined over the past year that reveal new and exciting roles for this key tumor suppressor gene. These functions include regulation of senescence through specific gene silencing mechanisms, control of developmental processes in extra-embryonic tissues, maintaining tissue homeostasis and determining survival responses to chemotherapy.

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    • "It is known that in addition to E2F-bound pRb, free unphosphorylated pRb accumulates after cells reach a post-mitotic state and it is this free active pRb that is responsible for driving and sustaining the various aspects of differentiation (Lipinski and Jacks, 1999). pRb has been intimately linked to the differentiation of several cell types such as cerebellar granule cells, adipocytes, keratinocytes, myoblasts and osteoblasts (Classon et al., 2000; Landsberg et al., 2003; Liu et al., 2004; Marino et al., 2003). pRb's participation in myogenic, adipogenic and osteogenic differentiation has been particularly well-studied. "
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    • "Epidemiologic studies have shown that the retinoblastoma tumor suppressor protein RB is functionally inactivated in most human neoplasms (Liu et al., 2004) with loss of heterozygosity being frequently observed in hepatocellular carcinomas (Ashida et al., 1997; Kondoh et al., 2001). In good agreement with the epidemiologic observations, mice with a liver-specific ablation of the Rb gene showed aberrant ploidy and increased multiplicity of liver tumors when exposed to DEN (Mayhew et al. 2005; Mayhew et al. 2007; Srinivasan et al. 2007). "
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    ABSTRACT: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biologic and toxic effects of its xenobiotic ligands. In recent years it has become evident that in the absence of ligand the AHR promotes cell cycle progression and that its activation by high-affinity ligands results in interactions with the retinoblastoma protein (RB) that lead to perturbation of the cell cycle, G0/G1 arrest, diminished capacity for DNA replication and inhibition of cell proliferation. Hence, the AHR has diametrically opposed pro-proliferative and anti-proliferative functions that have yet to be reconciled at the molecular level. Work from our own and from other laboratories suggests that the AHR may function as a tumor suppressor gene that becomes silenced in the process of tumor formation. To develop preliminary support for a more thorough examination of this hypothesis we characterized the expression levels of various tumor suppressor genes, transforming growth factor-beta (Tgfb) genes and the Ahr gene in liver tumor samples from mice with a liver-specific RB ablation and their wild-type littermates. In tumors arising in RB-positive livers, Cdkn2d and Tgfb1 were repressed and Cdkn2c, Tgfb2, Tgfb3 and Pai1 were induced, whereas in RB-negative tumors, only Cdkn2c and Tgfb3 were induced. Ahr was significantly repressed in tumors from both sets of mice, supporting the concept that Ahr silencing may be associated with cancer progression.
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    • "The mechanism by which RB inhibits cell proliferation is well established. RB interacts with E2F to repress transcription of genes critical for cell cycle progression (Liu et al., 2004; Nguyen and McCance, 2005). The ectopic cell proliferation in Rb-null embryos is suppressed by the knockout of E2f1 or E2f3, providing in vivo evidence for the critical role of RB in the control of E2F activity (Tsai et al., 1998; Ziebold et al., 2001). "
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    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.
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