The Retinoblastoma Gene Product (Rb) Induces Binding of a Conformationally Inactive Nuclear Factor-κB

Tamami, Mehrnaz; Lindholm, Paul F.; Brady, John

doi:10.1074/jbc.271.40.24551

Cited by 17 publications

(14 citation statements)

References 36 publications

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“…For example, NF-B regulates the expression of cyclinD1, a binding partner required for CDK4/6 activation. It also interacts directly with pRb, stimulating NF-B DNA binding, but suppresses transcriptional activity (Tamami et al, 1996). Similarly, NF-B potentially can regulate p53-mediated processes.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Factor-κB Modulates the p53 Response in Neurons Exposed to DNA Damage

Aleyasin¹,

Cregan²,

Iyirhiaro³

et al. 2004

J. Neurosci.

111

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Previous studies have shown that DNA damage-evoked death of primary cortical neurons occurs in a p53 and cyclin-dependent kinasedependent (CDK) manner. The manner by which these signals modulate death is unclear. Nuclear factor-B (NF-B) is a group of transcription factors that potentially interact with these pathways. Presently, we show that NF-B is activated shortly after induction of DNA damage in a manner independent of the classic IB kinase (IKK) activation pathway, CDKs, ATM, and p53. Acute inhibition of NF-B via expression of a stable IB mutant, downregulation of the p65 NF-B subunit by RNA interference (RNAi), or pharmacological NF-B inhibitors significantly protected against DNA damage-induced neuronal death. NF-B inhibition also reduced p53 transcripts and p53 activity as measured by the p53-inducible messages, Puma and Noxa, implicating the p53 tumor suppressor in the mechanism of NF-B-mediated neuronal death. Importantly, p53 expression still induces death in the presence of NF-B inhibition, indicating that p53 acts downstream of NF-B. Interestingly, neurons cultured from p65 or p50 NF-B-deficient mice were not resistant to death and did not show diminished p53 activity, suggesting compensatory processes attributable to germline deficiencies, which allow p53 activation still to occur. In contrast to acute NF-B inhibition, prolonged NF-B inhibition caused neuronal death in the absence of DNA damage. These results uniquely define a signaling paradigm by which NF-B serves both an acute p53-dependent pro-apoptotic function in the presence of DNA damage and an anti-apoptotic function in untreated normal neurons.

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Section: Discussionmentioning

confidence: 99%

Nuclear Factor-κB Modulates the p53 Response in Neurons Exposed to DNA Damage

Aleyasin¹,

Cregan²,

Iyirhiaro³

et al. 2004

J. Neurosci.

111

View full text Add to dashboard Cite

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“…It is intriguing to speculate that these mechanisms may crosstalk with the RB/E2F1-mediated AR regulation identified here. For example, RB can suppress NF-κB signaling (35), and E2F1 binds to and promotes activity of the Rel-A subunit (36). Twist1 is a candidate RB/E2F1 target gene (37) and has been implicated in PCa progression (38).…”

Section: Figurementioning

confidence: 99%

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

et al. 2010

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Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control. In analyses of human prostate cancer samples, RB loss was infrequently observed in primary disease and was predominantly associated with transition to the incurable, castration-resistant state. Further analyses revealed that loss of the RB1 locus may be a major mechanism of RB disruption and that loss of RB function was associated with poor clinical outcome. Modeling of RB dysfunction in vitro and in vivo revealed that RB controlled nuclear receptor networks critical for tumor progression and that it did so via E2F transcription factor 1-mediated regulation of androgen receptor (AR) expression and output. Through this pathway, RB depletion induced unchecked AR activity that underpinned therapeutic bypass and tumor progression. In agreement with these findings, disruption of the RB/E2F/nuclear receptor axis was frequently observed in the transition to therapy resistance in human disease. Together, these data reveal what we believe to be a new paradigm for RB function in controlling prostate tumor progression and lethal tumor phenotypes. IntroductionRetinoblastoma (RB; encoded by RB1), a tumor suppressor protein, is a critical negative regulator of tumor development. RB prevents tumorigenesis by suppressing cell cycle progression (1). However, the role of RB in tumor progression is poorly understood, and the clinical importance of RB loss during this process has not been well considered. Here, we identified a clinically relevant function for RB in tumor progression, manifest through control of hormone signaling networks.The function of RB in cell cycle control has been well described (1). Conditions favoring cell cycle arrest induce RB hypophosphorylation and activation. Active RB binds to promoters of genes required for S-phase entry (e.g., CCNA2 and MCM7) and, through association with the SWI/SNF complex and corepressor molecules (e.g., Sin3B), elicits transcriptional corepression. Many RB target genes are positively regulated by activator E2F transcription factors, supporting the current model that RB acts by suppressing E2F-mediated transcriptional activation. Indeed, the minimal transcriptional repression and tumor suppression domain of RB contains the E2F binding motif. E2F-independent functions of RB have been identified (2), but the contribution of these functions to tumor suppression is uncertain. Thus, contemporary views of RB suggest that the protein prevents cell cycle deregulation and tumor development through suppression of activator E2Fs.

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“…At present, the list of pRb-interacting factors numbers Ͼ110 (Morris and Dyson, 2001). At least two pRbinteracting factors, nuclear factor-B (NFB; Tamami et al, 1996) and c-Jun kinase (JNK; Chauhan et al, 1999;Shim et al, 2000), have been described that also are modulated by p53. Interestingly, Vousden and colleagues (Ryan et al, 2000) reported that p53-mediated death requires NFB activity.…”

Section: Cdks and P53 Cooperate To Mediate Bax Activation Cytochromementioning

confidence: 99%

Cyclin-Dependent Kinases and P53 Pathways Are Activated Independently and Mediate Bax Activation in Neurons after DNA Damage

et al. 2001

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DNA damage has been implicated as one important initiator of cell death in neuropathological conditions such as stroke. Accordingly, it is important to understand the signaling processes that control neuronal death induced by this stimulus. Previous evidence has shown that the death of embryonic cortical neurons treated with the DNA-damaging agent camptothecin is dependent on the tumor suppressor p53 and cyclin-dependent kinase (CDK) activity and that the inhibition of either pathway alone leads to enhanced and prolonged survival. We presently show that p53 and CDKs are activated independently on parallel pathways. An increase in p53 protein levels, nuclear localization, and DNA binding that result from DNA damage are not affected by the inhibition of CDK activity. Conversely, no decrease in retinoblastoma protein (pRb) phosphorylation was observed in p53-deficient neurons that were treated with camptothecin. However, either p53 deficiency or the inhibition of CDK activity alone inhibited Bax translocation, cytochrome c release, and caspase-3-like activation. Taken together, our results indicate that p53 and CDK are activated independently and then act in concert to control Bax-mediated apoptosis.

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The Retinoblastoma Gene Product (Rb) Induces Binding of a Conformationally Inactive Nuclear Factor-κB

Cited by 17 publications

References 36 publications

Nuclear Factor-κB Modulates the p53 Response in Neurons Exposed to DNA Damage

Nuclear Factor-κB Modulates the p53 Response in Neurons Exposed to DNA Damage

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

Cyclin-Dependent Kinases and P53 Pathways Are Activated Independently and Mediate Bax Activation in Neurons after DNA Damage

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