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: 7.57).
03/2004; 14(1):55-64. DOI: 10.1016/j.gde.2003.11.005
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.
Available from: Pedro G. Santiago-Cardona
- "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. "
Osteogenesis, 02/2012; , ISBN: 978-953-51-0030-0
Available from: Michal Stros
- "In conclusion, we have found that chromosomal proteins HMGB1 and HMGB2 could modulate cellular expression of topo IIα in cells lacking functional retinoblastoma gene susceptibility protein pRb by promoting binding of NF-Y to the topo IIα gene promoter. Our findings are discussed in the view of reported over-expression of HMGB1/2 proteins in tumors [(17) and refs therein], as well as the fact that the Rb gene is deleted/mutated in >50% human cancers (42). "
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ABSTRACT: Topoisomerase IIα (topo IIα) is a nuclear enzyme involved in several critical processes, including chromosome replication,
segregation and recombination. Previously we have shown that chromosomal protein HMGB1 interacts with topo IIα, and stimulates
its catalytic activity. Here we show the effect of HMGB1 on the activity of the human topo IIα gene promoter in different cell lines. We demonstrate that HMGB1, but not a mutant of HMGB1 incapable of DNA bending, up-regulates
the activity of the topo IIα promoter in human cells that lack functional retinoblastoma protein pRb. Transient over-expression of pRb in pRb-negative
Saos-2 cells inhibits the ability of HMGB1 to activate the topo IIα promoter. The involvement of HMGB1 and its close relative, HMGB2, in modulation of activity of the topo IIα gene is further supported by knock-down of HMGB1/2, as evidenced by significantly decreased levels of topo IIα mRNA and protein. Our experiments suggest a mechanism of up-regulation of cellular expression of topo IIα by HMGB1/2 in pRb-negative
cells by modulation of binding of transcription factor NF-Y to the topo IIα promoter, and the results are discussed in the framework of previously observed pRb-inactivation, and increased levels of
HMGB1/2 and topo IIα in tumors.
Nucleic Acids Research 03/2009; 37(7):2070-86. DOI:10.1093/nar/gkp067 · 9.11 Impact Factor
Available from: Michael Schnekenburger
- "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.
Toxicology 05/2008; 246(2-3):242-7. DOI:10.1016/j.tox.2008.01.002 · 3.62 Impact Factor
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