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The RB tumor suppressor positively regulates transcription of the anti-angiogenic protein NOL7.

ABSTRACT: The expression of the angiogenic phenotype is regulated by a balance of pro-angiogenic and anti-angiogenic factors released into the tumor microenvironment. Nuclear protein 7 (NOL7), a novel tumor suppressor, acts as a master regulator of angiogenesis by downregulating pro-angiogenic factors and upregulating anti-angiogenic factors. Using cervical cancer as a model of investigation, we have previously shown that loss of NOL7 mRNA and protein expression is observed as early as the premalignant phase. Analysis of the gene failed to identify tumor-specific promoter methylation or coding region mutations, suggesting that NOL7 loss may be mediated by aberrant expression of its upstream regulators. In this study, we show that the RB tumor suppressor gene (RB) positively regulates NOL7 at the transcriptional level by recruiting transcription factors and transcription machinery proteins to its promoter region. Conversely, the loss of RB represses NOL7 transcription by inhibiting assembly of these proteins. This loss of NOL7 expression is also observed in RB-deficient human malignancies. Together, this work further characterizes the transcriptional activator function of RB and defines a potential role for RB in regulating angiogenesis through activation of NOL7. Current anti-angiogenic therapies lack long-term efficacy, as they are unable to target the diverse angiogenic signals generated by tumors. Our data provide evidence to support the hypothesis that reactivation of pRB can potentially modulate the expression of the angiogenic phenotype through regulation of NOL7. Therefore, this knowledge may be employed to design more comprehensive and effective therapies.

SUBMITTER: Mankame TP

PROVIDER: S-EPMC3540946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of cell cycle-promoting transcription factors. Because the de novo synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1 and Rbl2) and found that loss of global Rb function caused a marked increase in (13)C-glutamine uptake and incorporation into glutamate and tricarboxylic acid cycle (TCA) intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption, whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the wild-type (WT) MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate ?-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly regulates a major energetic and anabolic pathway that is required for neoplastic growth.

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The RB tumor suppressor positively regulates transcription of the anti-angiogenic protein NOL7.

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