ARF Directly Binds DP1: Interaction with DP1 Coincides with the G<sub>1</sub> Arrest Function of ARF

Datta, Abhishek; Sen, Jyoti Misra; Hagen, Jussara; Korgaonkar, Chandrashekhar K.; Caffrey, Michael; Quelle, Dawn E.; Hughes, Douglas E.; Ackerson, Timothy; Costa, Robert H.; Raychaudhuri, Pradip

doi:10.1128/mcb.25.18.8024-8036.2005

Cited by 46 publications

(39 citation statements)

References 65 publications

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“…ARF binds to MDM2 to activate the growth-suppressive functions of p53 but can also exert its tumor suppressor activity independently of p53; for example, ARF has been shown to inhibit the transcriptional activity of E2F1 through regulation on both E2F and DP1 (64,65). More recently, ARF has been shown to inhibit ribosomal RNA processing and to specifically interact with the rRNA promoter (66) and inhibit rRNA transcription by blocking upstream binding factor phosphorylation (67).…”

Section: Discussionmentioning

confidence: 99%

Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

Paik

Wang

Liu

et al. 2010

Journal of Biological Chemistry

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Regulation of the E2F family of transcription factors is important in control of cellular proliferation; dysregulation of the E2Fs is a hallmark of many cancers. One member of the E2F family, E2F1, also has the paradoxical ability to induce apoptosis; however, the mechanisms underlying this selectivity are not fully understood. We now identify a nucleolar protein, RRP1B, as an E2F1-specific transcriptional target. We characterize the RRP1B promoter and demonstrate its selective response to E2F1. Consistent with the activation of E2F1 activity upon DNA damage, RRP1B is induced by several DNA-damaging agents. Importantly, RRP1B is required for the expression of certain E2F1 proapoptotic target genes and the induction of apoptosis by DNA-damaging agents. This activity is mediated in part by complex formation between RRP1B and E2F1 on selective E2F1 target gene promoters. Interaction between RRP1B and E2F1 can be found inside the nucleolus and diffuse nucleoplasmic punctates. Thus, E2F1 makes use of its transcriptional target RRP1B to activate other genes directly involved in apoptosis. Our data also suggest an underappreciated role for nucleolar proteins in transcriptional regulation.E2F1 is a critical regulator of DNA damage response and apoptosis. As part of the E2F family of transcription factors, E2F1 is also involved in regulation of a wide array of genes important for cell cycle progression and other functions (1). Paradoxically, E2F1 has the unique ability to induce apoptosis (2). Overexpression of E2F1 ex vivo leads to apoptosis of breast cancer and other cells (3-5). Deletion of E2F1 in vivo shows a defect in thymocyte apoptosis and increased tumor incidence (6, 7). An endogenous role for E2F1 apoptosis is illustrated by its activation and stabilization by genotoxic stimuli. Overexpression of E2F1 sensitizes cells to radiation and chemotherapy (8, 9). DNA damage activates E2F1 expression and induces E2F1 stabilization through phosphorylation by DNA damage-responsive kinases ATM (ataxia telangiectasia mutated) (10) and Chk2 (checkpoint kinase 2) (11) and through acetylation (12, 13). E2F1 transactivates proapopotic genes, such as p73 (14, 15), Apaf-1 (16), and caspases (16) independently of p53 and cooperates with p53 through transactivation of p19 ARF (17). Investigation of how E2F1 specifically regulates apoptosis through selective transcriptional regulation vis-à-vis other E2F family members may reveal targets for future study that might improve the sensitivity of cancer to radiotherapy and chemotherapy. We therefore attempted to identify genes specifically regulated by E2F1 that potentially regulate E2F1-induced apoptosis. Previously, the Helin group published a microarray data set in which expression profiles were compared between cells that overexpressed E2F1, E2F2, and E2F3 (18). We screened their data set to include only those genes that were significantly induced by E2F1 but whose expression did not change more than 1-fold either positively or negatively upon E2F2 or E2F3 overexpression. The list o...

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Section: Discussionmentioning

confidence: 99%

Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

Paik

Wang

Liu

et al. 2010

Journal of Biological Chemistry

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“…However, an increasing number of studies now points to the fact that not all ARF tumor suppressor functions are elicited through the p53-Mdm2 pathway. These new aspects of p53-independent ARF functions have been supported mainly by the characterization of a wide range of new ARF binding partners, such as the B23/nucleophosmin protein involved in ribosome biogenesis (7,20), the E2F-1 transcription factor (14) and its cofactor DP1 (12) involved in S phase progression, and the recently identified E3 ubiquitin ligase ARF-BP1/Mule (10). In contrast, the cellular signaling pathways involved in these new functions of ARF remain largely unknown.…”

Section: Arf (Known As P14mentioning

confidence: 94%

p14^ARF Activates a Tip60-Dependent and p53-Independent ATM/ATR/CHK Pathway in Response to Genotoxic Stress

Eymin

Claverie

Salon

et al. 2006

Molecular and Cellular Biology

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p14ARF is a tumor suppressor that controls a well-described p53/Mdm2-dependent checkpoint in response to oncogenic signals. Here, new insights into the tumor-suppressive function of p14 ARF are provided. We previously showed that p14 ARF can induce a p53-independent G 2 cell cycle arrest. In this study, we demonstrate that the activation of ATM/ATR/CHK signaling pathways contributes to this G 2 checkpoint and highlight the interrelated roles of p14 ARF and the Tip60 protein in the initiation of this DNA damage-signaling cascade. We show that Tip60 is a new direct p14 ARF binding partner and that its expression is upregulated and required for ATM/CHK2 activation in response to p14 ARF . Strikingly, both p14 ARF and Tip60 products accumulate following a cell treatment with alkylating agents and are absolutely required for ATM/CHK2 activation in this setting. Moreover, and consistent with p14 ARF being a determinant of CHK2 phosphorylation in lung carcinogenesis, a strong correlation between p14 ARF and phospho-CHK2 (Thr68) protein expression is observed in human lung tumors (P < 0.00006). Overall, these data point to a novel regulatory pathway that mediates the p53-independent negative-cell-growth control of p14 ARF . Inactivation of this pathway is likely to contribute to lung carcinogenesis.

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“…S2B), we selected nine downregulated genes with a cutoff value of <1.5, associated with cell-cycle progression and identified by both bioinformatic platforms (Table 1). In agreement with the role of TRAP1 in regulating cell-cycle progression, these genes are all responsible for the regulation of G 0 -G 1 and/or G 2 -M transitions (28)(29)(30)(31)(32)(33)(34)(35), with most of them activated by ERK signaling (36). To validate the microarray data, the expressions of eight of these genes were analyzed by quantitative PCR and immunoblot analyses in scramble/shTRAP1 HCT116 cells (Fig.…”

Section: Trap1 Regulates Braf Synthesis/ubiquitination At Translationmentioning

confidence: 99%

TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors

et al. 2014

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Human BRAF-driven tumors are aggressive malignancies with poor clinical outcome and lack of sensitivity to therapies. TRAP1 is a HSP90 molecular chaperone deregulated in human tumors and responsible for specific features of cancer cells, i.e., protection from apoptosis, drug resistance, metabolic regulation, and protein quality control/ubiquitination. The hypothesis that TRAP1 plays a regulatory function on the BRAF pathway, arising from the observation that BRAF levels are decreased upon TRAP1 interference, was tested in human breast and colorectal carcinoma in vitro and in vivo. This study shows that TRAP1 is involved in the regulation of BRAF synthesis/ubiquitination, without affecting its stability. Indeed, BRAF synthesis is facilitated in a TRAP1-rich background, whereas increased ubiquitination occurs upon disruption of the TRAP1 network that correlates with decreased protein levels. Remarkably, BRAF downstream pathway is modulated by TRAP1 regulatory activity: indeed, TRAP1 silencing induces (i) ERK phosphorylation attenuation, (ii) cell-cycle inhibition with cell accumulation in G 0 -G 1 and G 2 -M transitions, and (iii) extensive reprogramming of gene expression. Interestingly, a genome-wide profiling of TRAP1-knockdown cells identified cell growth and cell-cycle regulation as the most significant biofunctions controlled by the TRAP1 network. It is worth noting that TRAP1 regulation on BRAF is conserved in human colorectal carcinomas, with the two proteins being frequently coexpressed. Finally, the dual HSP90/TRAP1 inhibitor HSP990 showed activity against the TRAP1 network and high cytostatic potential in BRAF-mutated colorectal carcinoma cells. Therefore, this novel TRAP1 function represents an attractive therapeutic window to target dependency of BRAF-driven tumors on TRAP1 translational/quality control machinery. Cancer Res; 74(22); 6693-704. Ó2014 AACR.

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ARF Directly Binds DP1: Interaction with DP1 Coincides with the G₁ Arrest Function of ARF

Cited by 46 publications

References 65 publications

Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

p14^ARF Activates a Tip60-Dependent and p53-Independent ATM/ATR/CHK Pathway in Response to Genotoxic Stress

TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors

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ARF Directly Binds DP1: Interaction with DP1 Coincides with the G1 Arrest Function of ARF

Cited by 46 publications

References 65 publications

Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

Regulation of E2F1-induced Apoptosis by the Nucleolar Protein RRP1B

p14ARF Activates a Tip60-Dependent and p53-Independent ATM/ATR/CHK Pathway in Response to Genotoxic Stress

TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors

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ARF Directly Binds DP1: Interaction with DP1 Coincides with the G₁ Arrest Function of ARF

p14^ARF Activates a Tip60-Dependent and p53-Independent ATM/ATR/CHK Pathway in Response to Genotoxic Stress