IndraLab
Statements
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"CDKs are positively regulated by cyclins (a, b, d and e), and negatively regulated by cyclin-dependent kinase inhibitors, such as p21 and p27. xref After being activated in the G1 phase, CyclinD1 can phosphorylate pRb, which in turn promotes cells to progress to the S phase. xref CyclinD1 plays an essential role in many cancers and cancer therapies. xref , xref Bao et al reported that upregulating the Hint1 expression causes cyclinD1 inhibition, which suppresses liver cancer cell proliferation. xref In the present study, it was found that Hint1 downregulated the cyclinD1 expression level, but not the P27 level, suggesting that cyclinD1 may be the target of Hint1."
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"Since cyclin D1-CDK4/6 complexes phosphorylate and inactivate Rb family proteins, p21 can indirectly activate Rb family proteins to inhibit the E2F1-dependent expression of mitotic regulators, thus halting the G2/M progression and resulting in the irreversible G2 arrest of cell cycle ( xref )."
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"Because RB hyperphosphorylation is principally triggered by cyclin D1, and cyclin A2/Cdk2 binding is required for cells to enter S-phase, we investigated both cyclin D1 and cyclin A2 expression level, registering a powerful reduction of both after 48 h from ONC administration, and this reduction was almost totally maintained for a further 24 h ( xref )."
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"Induction of miR-21 and miR-181b expression in sepsis Gr1 + CD11b + MDSCs is mediated by Rb phosphorylation by the cyclin D1–cdk4 protein complex. xref In these cells, phosphorylated Rb binds to and sequesters the C/EBPa protein, leading to Stat3 and C/EBPb binding to and activating of the miR-21 and miR-181b promoters. xref The Gr1 + CD11b + cells from the NFI-A conditional knockout mice did not express miR-21 and miR-181b ( xref )."
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"Together with CCND1, which leads to the hyperphosphorylation of the tumor suppressor protein retinoblastoma (pRb) and to its dissociation of the E2 promoter binding protein dimerization partners (E2F) from the pRb and E2F complex, CCNE1 is considered to be a key oncogene and is overexpressed in breast, liver, lung, and brain cancers [XREF_BIBR, XREF_BIBR]."
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"Phosphorylation of Rb, p107, and p130 by CDK4/6-cyclin D1 (encoded for by CCND1 ) complex inactivates the Rb proteins and allows E2F proteins to regulate transcription of the genes that encode for proteins necessary for S phase, including cyclin E. Cyclin D1 is present in early G 1 and its production is induced primarily by mitogenic growth factors [ xref ]; it is responsible for progressing the cell past the restriction point."
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"Taken together, these data strongly suggest that DN-PPAR γ regulates CASMC proliferation, at least in part, by inducing ERK 1/2 phosphorylation to activate cyclin D1 expression, and that the resulting cyclin D1-CDK4/6 complexes in turn phosphorylate Rb to promote G1→S progression."
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"In IPF fibroblasts subjected to UCP2 silencing, we observed an increase in cell proliferation with a concomitant induction of cyclin D1 and phosphorylated Rb, while the expression of myofibroblast differentiation markers, α‐smooth muscle actin (α‐SMA) and collagen 1a1 (COL1a1) was reduced (Figure xref )."
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"The phosphorylation of the RB1 protein by cyclin D1-CDK4/6 complexes plays an important role in cell advancement through the cell cycle and the regulation of the R-point: the unphosphorylated form is present in G0, hypophosphorylation correlates to entry into G1, and hyperphosphorylation is concurrent with passing of the restriction point and completion of the cell cycle."
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"Associated with its specific kinases, CDK4/6, cyclin D1 phosphorylates and inhibits the retinoblastoma protein (RB1), allowing the release of transcription factors of the E2F family, the transcriptional activation of genes controlling DNA synthesis, and the G1-to-S phase progression within the cell cycle [ xref ]."
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"To reveal why the upregulated CCND1-CDK4/6 complex does not promote phosphorylation of RB1 ( xref and xref ), we focused on the CKI (cyclin-dependent kinase inhibitor) and found that p21 (CDKN1A) was significantly upregulated by MG132 but not by p97 inhibitors ( xref and xref )."
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"We further revealed the molecular mechanism by which nuclear-localized GHR regulates MSCs proliferation, and found that nuclear-targeted GHR enhanced the phosphorylation of STAT5, and the activated STAT5 initiates the transcription of CyclinD1, after which, the complex of CyclinD1 and CDK4 further phosphorylates Rb, and the activated Rb releases E2F1, the released E2F1 ultimately realizes the biological function of GH promoting cell proliferation."
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"For example, HPV− HNSCC characteristically inactivates the cell cycle suppressors TP53 (p53) and CDKN2A (p16), and often amplifies CCND1 (cyclin D), which phosphorylates RB1 to promote cell cycle progression from G1 to S. By contrast, HPV+ HNSCC expresses viral oncogenes E6 and E7, which inhibit TP53 and RB1, and activates the cell cycle regulator E2F1."
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"Additionally, p53 triggers senescence by promoting the expression and secretion of the serine protease inhibitor plasminogen activator inhibitor‐1 (PAI‐1) which, via an autocrine function, prevents the cyclin D1‐dependent phosphorylation of Rb leading to cell growth arrest xref , xref , xref , xref , xref , xref ."
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"In this model, HBP1 binds to the CCND1 and CCND3 promoters and activates their transcription, HBP1 also binds to p16 INK4A promoter, but does not change its expression, though it does remove the inhibitory effect of p16 on CDK4, thus, CCND1-CDK4 and CCND3-CDK6 complexes facilitate the phosphorylation of p107 and pRB, respectively."
reach
"For example, HPV- HNSCC characteristically inactivates the cell cycle suppressors TP53 (p53) and CDKN2A (p16), and often amplifies CCND1 (cyclin D), which phosphorylates RB1 to promote cell cycle progression from G1 to S. By contrast, HPV+ HNSCC expresses viral oncogenes E6 and E7, which inhibit TP53 and RB1, and activates the cell cycle regulator E2F1."
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"Kim et al demonstrated that BVRA knockdown leads to marked reduction in the expression of cyclin D1 and phosphorylated pRb, whereas it increases the expression of p16 (member of INK4 family), leading to premature cellular senescence. xref Another inhibitor of the INK4 family of proteins, p18, which arrests the cell cycle at the G1 phase, was shown to be protective during cisplatin nephrotoxicity. xref Recent evidence also suggests that p18 expression is regulated by HO-1 expression, in that HO-1 upregulates p18 expression while inhibition of HO activity was found to ablate such induction during cisplatin injury. xref "