From G0 to S phase: A view of the roles played by the retinoblastoma (Rb) family members in the Rb‐E2F pathway

Sun, Ang; Bagella, Luigi; Tutton, Steven; Romano, Gaetano; Giordano, Antonio

doi:10.1002/jcb.21609

Cited by 132 publications

(133 citation statements)

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“…It is known that increases of Rb protein inhibits cell cycle progression and that Rb activities depend on its phosphorylation status (40). The hypophosphorylated Rb binds to E2F family proteins in a cell cycle-dependent manner to modulate proliferation (32,33). Blocking Rb-E2F interaction with its endogenous genes has been reported to prevent the Rbmediated growth arrest (41), and this probably involves the recruitment of other repressors (e.g., HDAC) to the Rb-E2F complex (42).…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study showed that steady laminar shear causes dephosphorylation of Rb protein (3). Rb in its hypophosphorylation state binds to E2F family proteins and suppresses cell proliferation by inhibiting the cell cycle progression through G1 into S phase and preventing DNA synthesis (32,33). Twentyfour-hour PS decreased Rb phosphorylation without affecting the total Rb expression (Fig.…”

Section: Long-term Pulsatile Laminar Flow Keeps Vascular Endothelium mentioning

confidence: 96%

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Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth

Wang

Garmire

Young

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

158

130

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MicroRNAs (miRs) can regulate many cellular functions, but their roles in regulating responses of vascular endothelial cells (ECs) to mechanical stimuli remain unexplored. We hypothesize that the physiological responses of ECs are regulated by not only mRNA and protein signaling networks, but also expression of the corresponding miRs. EC growth arrest induced by pulsatile shear (PS) flow is an important feature for flow regulation of ECs. miR profiling showed that 21 miRs are differentially expressed (8 up-and 13 downregulated) in response to 24-h PS as compared to static condition (ST). The mRNA expression profile indicates EC growth arrest under 24-h PS. Analysis of differentially expressed miRs yielded 68 predicted mRNA targets that overlapped with results of microarray mRNA profiling. Functional analysis of miR profile indicates that the cell cycle network is highly regulated. The upregulation of miR-23b and miR-27b was found to correlate with the PS-induced EC growth arrest. Inhibition of miR-23b using antagomir-23b oligonucleotide (AM23b) reversed the PSinduced E2F1 reduction and retinoblastoma (Rb) hypophosphorylation and attenuated the PS-induced G1/G0 arrest. Antagomir AM27b regulated E2F1 expression, but did not affect Rb and growth arrest. Our findings indicate that PS suppresses EC proliferation through the regulation of miR-23b and provide insights into the role of miRs in mechanotransduction.cell cycle | shear | bioinformatics | gene regulation | mechanotransduction H emodynamic forces, e.g., stretch and shear stress, act constantly on the vascular endothelial cells (ECs) to modulate EC signaling, gene expression, and physiological functions (1). Atherosclerotic lesions in the arterial tree are found mainly at branch points, where blood flow is disturbed with a limited forwarding direction, but are generally spared at the straight parts of the arterial tree, where the flow is laminar with a large forwarding direction (2). Exposure of ECs to 24 h of steady laminar shear flow at 12 dyn/cm 2 (approximating the hemodynamic force in straight parts of arteries) leads to antiproliferative (3) and antiinflammatory (4) responses. In contrast, ECs exposed to disturbed flow, mimicking the hemodynamic force at branch points, exhibit opposite responses (5, 6). The laminar shear-induced EC growth arrest involves the expression of CDK inhibitors (e.g., p21 cip , p27 kip ), tumor suppressor p53, and retinoblastoma (Rb) hypophosphorylation (3, 7). Whereas there is considerable knowledge on mechanotransduction at protein and mRNA levels, there is little information on the role of microRNAs (miRs) in this process.miRs are small noncoding RNAs (∼21-25 nucleotides) that regulate gene expression by binding to target mRNAs to cause their degradation or translational repression (8). It is estimated that miRs regulate ∼30% of human protein-coding genes. More than 800 miRs have been identified in the human genome and registered in the Sanger miRBase. These small RNAs provide a powerful mechanism for posttranscriptional cont...

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Section: Discussionmentioning

confidence: 99%

Section: Long-term Pulsatile Laminar Flow Keeps Vascular Endothelium mentioning

confidence: 96%

Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth

Wang

Garmire

Young

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

158

130

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“…The retinoblastoma gene encodes the Rb protein which, in its unphosphorylated state, blocks transition from G 1 to S phase in the cell cycle and is necessary for prevention of cell replication when DNA has been damaged (32). In 51 intra-hepatic and 34 extrahepatic CCs no correlation between Rb expression and survival could be shown (33,34).…”

Section: P53 [Table 1]mentioning

confidence: 99%

Prognostic molecular markers in cholangiocarcinoma: A systematic review

Briggs

Neal

Mann

et al. 2009

European Journal of Cancer

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The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, the United Kingdom incidence now exceeding 1000 cases per year. It is an aggresive malignancy typified by unresponsiveness to existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though postoperative disease recurrence is common, with 5-year survival rates following resection of less then 25%. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP, and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.

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“…miR-23a regulates cardiomyocyte growth, 35 whereas miR-23b targets E2F1, a transcription factor in eukaryotes and plays a proangiogenic role. 36 Additionally, miR-23 is reported to repress TGF-β-induced endothelial-to-mesenchymal transition, a process that regulates the origin of fibroblasts from endothelial cells, which indicates its potential as an antifibrotic mediator. 37 miR-27a/b regulates myocardial neovascularization after ischemia by targeting the 3′-untranslated regions of semaphorin 6A (SEMA6A), which has been found to inhibit growth factor-and tumor cell line-induced neovascularization.…”

Section: Mir-24 Familymentioning

confidence: 99%