Chronic Inflammation Promotes Retinoblastoma Protein Hyperphosphorylation and E2F1 Activation

Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, United States
Cancer Research (Impact Factor: 9.33). 11/2005; 65(20):9132-6. DOI: 10.1158/0008-5472.CAN-05-1358
Source: PubMed


Chronic inflammation contributes to tumorigenesis. The retinoblastoma protein (pRb), in its hyperphosphorylated form, releases E2 promoter binding factor-1 (E2F1), which drives cell proliferation. Here, we show that pRb is hyperphosphorylated in both mouse and human colitis. In turn, pRb hyperphosphorylation is associated with release of E2F1 from pRb, resulting in the activation of E2F1 target molecules involved in proliferation and apoptosis. These observations provide insight into the in vivo mechanisms associated with chronic colon inflammation and increased colon cancer risk.

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Available from: Dan A Dixon, Mar 11, 2014
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    • "In agreement with our findings, Sturm et al. [17] observed that colonic T cells obtained from CD patients show increased RB phosphorylation than UC-derived T cells. Moreover, DSS-induced colitis increased RB phosphorylation and inactivation in the colonic mucosa [35], [36], resulting in increased proliferation through the E2F1 pathway. This RB hyperphosphorylation is mediated by nitric oxide and is dependent of MEK/ERK (mitogen activated protein kinase/extracellular signal-regulated kinase kinase and PI3K (phosphatidylinositol 3-kinase)/AKT pathways [36]. "
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    ABSTRACT: In about 10-15% of patients with inflammatory bowel diseases (IBD) there is no clear definitive differential diagnosis between Crohn's disease (CD) and ulcerative colitis (UC) and the disease is classified as indeterminate colitis. Since pharmacological and surgical treatments differ in CD and UC, establishing a correct diagnosis is critical. The aim of this work was to access the expression profile of proteins involved in colonic inflammation and cancer in samples from CD and UC. For that, colon samples from 24 CD, 21 UC and 10 control patients were processed for immunohistochemistry using anti-phosphorylated RB at Ser(807/811) and anti-β-catenin. Crypts were blinded, analyzed and counted for phosphorylated RB-positive (phospho-RB) cells or scored for positive β-catenin staining. Western blot was used for confirming immuhistochemical results: RB phosphorylation was significantly greater in colon samples from patients with CD compared with UC (p<0.005). In contrast, the expression of β-catenin was significantly increased in UC compared with CD (p<0.005) samples. Phospho-RB and β-catenin are negatively correlated (CC: -0.573; p = 0.001). A positive phospho-RB test yielded high levels of sensitivity, specificity, negative and positive predictive values, and accuracy for the diagnosis of CD against UC. This work indicates that RB phosphorylation and β-catenin nuclear translocation are differently expressed in CD and UC, and provide novel insights into the pathogenic mechanisms of IBD. In particular, rates of phospho-RB-positive cells in mucosal samples emerge as a promising tool for the differential diagnosis of patients with IBD.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "Western blots were carried out as described previously [42]. Antibodies used include: p53 (mouse monoclonal, DO-1, diluted 1 in 500, cat# OP43T; Calbiochem, Gibbstown, NJ, USA) and GAPDH (Rabbit monoclonal, diluted 1 in 1000, cat# 5174 P; Cell Signaling Technology, Danvers, MA, USA). "
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    ABSTRACT: Ulcerative colitis (UC) is debilitating and carries a high colon cancer risk. Apoptosis of inflammatory cells is a key mechanism regulating UC. We have recently shown that American ginseng (AG), and to a greater extent, a Hexane fraction of AG (HAG) can cause apoptosis and suppress mouse colitis through a p53-mediated mechanism. Here, we tested the hypothesis that HAG suppresses colitis through a p53 mechanism. We found only a limited impact of p53 in the ability of HAG to induce inflammatory cell apoptosis and suppress mouse colitis in vitro and in vivo. Finally, we asked whether HAG could cause cell cycle arrest of HCT116 colon cancer cells in vitro. Interestingly, HAG caused a G1 arrest of such cells independent of p53 status. Findings are significant because HAG suppresses colitis and associated colon cancer, and mutation in p53 is observed in most colitis-driven colon cancers. Therefore, HAG might be very effective in targeting the inflammatory cells and cancer cells since it induces apoptosis of inflammatory cells and cell cycle arrest in both p53-/- and WT p53 colon cancer cells.
    Full-text · Article · Jul 2012 · BioMed Research International
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    • "The participation of E2F1 suggests that the transcription of these NF-kB target genes may also be modulated by molecular events that alter E2F1 activity. Some immunologically relevant biological stimuli that are known to regulate E2F1 activity include viral infection (Helt and Galloway, 2003), chronic inflammation (Ying et al., 2005), and transforming growth factor beta (TGF-b) (Herrera et al., 1996). Our finding therefore opens up the possibility of crosstalk between the E2F1 and NF-kB signaling pathways that will add another layer of control and specificity to the transcriptional network of the innate immune response. "
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    ABSTRACT: NF-kappaB is a key mediator of inflammation. Here, we mapped the genome-wide loci bound by the RELA subunit of NF-kappaB in lipopolysaccharide (LPS)-stimulated human monocytic cells, and together with global gene expression profiling, found an overrepresentation of the E2F1-binding motif among RELA-bound loci associated with NF-kappaB target genes. Knockdown of endogenous E2F1 impaired the LPS inducibility of the proinflammatory cytokines CCL3(MIP-1alpha), IL23A(p19), TNF-alpha, and IL1-beta. Upon LPS stimulation, E2F1 is rapidly recruited to the promoters of these genes along with p50/RELA heterodimer via a mechanism that is dependent on NF-kappaB activation. Together with the observation that E2F1 physically interacts with p50/RELA in LPS-stimulated cells, our findings suggest that NF-kappaB recruits E2F1 to fully activate the transcription of NF-kappaB target genes. Global gene expression profiling subsequently revealed a spectrum of NF-kappaB target genes that are positively regulated by E2F1, further demonstrating the critical role of E2F1 in the Toll-like receptor 4 pathway.
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