Elevated Poly-(ADP-Ribose)-Polymerase Activity Sensitizes Retinoblastoma-Deficient Cells to DNA Damage-Induced Necrosis

The Ben May Department for Cancer Research, The Gordon Center for Integrative Sciences, The University of Chicago, Chicago, Illinois 60637, USA.
Molecular Cancer Research (Impact Factor: 4.38). 08/2009; 7(7):1099-109. DOI: 10.1158/1541-7786.MCR-08-0439
Source: PubMed


The retinoblastoma (Rb) tumor suppressor is a key regulator of cell cycle checkpoints but also protects against cell death induced by stresses such as DNA damage and death receptor ligation. We report here that cell death of Rb-deficient cells exposed to key genotoxic agents was associated with increased expression of S phase-specific E2F target genes and cell death consistently occurred in the S phase of the cell cycle. Cell cycle arrest induced by serum starvation prevented S phase entry, attenuated DNA damage, and promoted survival, suggesting that Rb-null cells die due to a failure to prevent S phase entry. DNA damage-induced death of Rb-null cells was associated with nucleotide depletion, higher activity of poly-ADP-ribose-polymerase (Parp), and cell death that was primarily necrotic. Knockdown of Parp-1 or chemical inhibition of Parp activity prevented nucleotide depletion and restored the viability of Rb-deficient cells to wild-type levels. Furthermore, chemical inhibition of Parp activity in vivo attenuated the cytotoxic effects of cisplatin against Rb-deficient tumors, arguing that Parp inhibitors should not be used therapeutically in combination with genotoxic drugs against tumors that are inactivated for the Rb tumor suppressor.

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    • "The cell cycle dependent transcription of the E-cyclins is mediated by E2F transcription factors, which are activated via release from Rb during late G1 phase. Rb-deficient cells have high expression of cyclin E1 and cyclin E2 [45,54], likely due to constitutive E2F release, and numerous gene expression array studies have confirmed both CCNE1 and CCNE2 as E2F1, E2F2 and E2F3 target genes [55-57]. E2F proteins interact with multiple co-regulators at the E-cyclin promoters, allowing for the input of mitogenic signals. "
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    ABSTRACT: The highly conserved E-type cyclins are core components of the cell cycle machinery, facilitating the transition into S phase through activation of the cyclin dependent kinases, and assembly of pre-replication complexes on DNA. Cyclin E1 and cyclin E2 are assumed to be functionally redundant, as cyclin E1-/- E2-/- mice are embryonic lethal while cyclin E1-/- and E2-/- single knockout mice have primarily normal phenotypes. However more detailed studies of the functions and regulation of the E-cyclins have unveiled potential additional roles for these proteins, such as in endoreplication and meiosis, which are more closely associated with either cyclin E1 or cyclin E2. Moreover, expression of each E-cyclin can be independently regulated by distinct transcription factors and microRNAs, allowing for context-specific expression. Furthermore, cyclins E1 and E2 are frequently expressed independently of one another in human cancer, with unique associations to signatures of poor prognosis. These data imply an absence of co-regulation of cyclins E1 and E2 during tumorigenesis and possibly different contributions to cancer progression. This is supported by in vitro data identifying divergent regulation of the two genes, as well as potentially different roles in vivo.
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    ABSTRACT: The RB-pathway, consisting of inhibitors and activators of cyclin-dependent kinases, the retinoblastoma tumor suppressor (RB), and the E2F-family of transcription factors, plays critical roles in the regulation of cell cycle progression and cell death. Components of this pathway, particularly p16Ink4a, cyclin D1, and RB, are frequently altered in sporadic human cancers to promote deregulated cellular proliferation. The consistent disruption of the RB-pathway in human cancers raises the possibility of exploiting tumor-specific RB-pathway defects to improve the efficacy of current therapies and to develop new therapeutic strategies. This article discusses how the RB-pathway status impacts the cellular responses to cytotoxic, cytostatic, and hormone therapies, and how the components of the RB-pathway may be directly targeted to treat cancer.
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