ii. DNA Damage In normal cells p53 is usually inactive, bound to MDM2 protein that inhibits the protein and promotes the degradation of functioning as a ubiquitin ligase. The activation of p53 is induced after the effects of various carcinogens such as UV, oncogenes and drugs or other substances that damage DNA. The damage to DNA are found in specific "stages" Control of cell cycle proteins that induce various-such as ATM, Chk1 and Chk2-to phosphorylate p53 sites near or within the region that binds MDM2 (inhibiting the attack). Even oncogenes stimulate the activation of p53 by p14ARF protein. Somne other oncogenes, however, stimulate the transcription of a protein that inhibits MDM2. Once activated, p53 activates the transcription of many genes including that for p21, which binds the complex G1-S/OCDK and D/CDK (molecules important for the transition from G1 to S phase) by inhibiting their activity ( and avoiding the proliferation of mutated cells). Another important function of p53 tumor suppression is inhibition of angiogenesis. 1.3 Activation of Proliferation IGF1 an FGF2: They are coordinately enhance cyclin D1 and cyclin E-cdk2 association and activity to promote G1 progression in oligodendrocyte progenitor cells. Insulin-like growth factor (IGF)-I and fibroblast growth factor (FGF)-2 have known functions individually in development of neural stem cells as well as more restricted neuronal and glial progenitor cells. IGF-I enhanced FGF-2 induction of cyclin D1, activation of G(1) cyclin-cyclin- dependent kinase (cdk) complexes, and hyperphosphorylation of retinoblastoma protein (PRb). Besides, IGF-I was required for G(2)/M progression. In contrast, FGF-2 decreased levels of the cdk inhibitor p27(Kip1) associated with cyclin E-cdk2. PDGF: Exposure to PDGF, which stimulates cell cycle entry but not progression through G Graphic, induces the formation of cyclin D Graphic-Cdk4 complexes that bind p27 Graphic and titrate the pool of Kip1 available to inhibit Cdk2. In addition, PDGF stimulates a moderate transient reduction in the abundance of p27 Graphic protein. However, limited expression of cyclin E and cyclin A is observed after PDGF treatment, and in the absence of PPP, p27 levels are suficient to bind and inactivate existing cyclin-Cdk complexes. . Contact Us : Website : www.eduncle.com | Email : email@example.com | Call Toll Free: 1800-120-1021 4 Eduncle Biotechnology (Sample Theory) Although plasma does not significantly increase the proportion of Kip1 bound to cyclin D Graphic-Cdk4, stimulation of PDGF-treated cells with plasma does overcome the threshold inhibition of p27 Graphic by further increasing the expression of cyclins E and A and decreasing the amount of Kip1 over a prolonged time period. SCE CDK4/6 CDK2 cyclinE >Ubiquitination Ubiquitination ** S-PHASE G1-PHASE o Cell Signali Suv39H1 E2F/DP Target Genes: cyclin E/A, E2F-1/2/3. coc2, c-Myc, p107, AblRb HDAC Rb FoxO1 Bim E2 DP-1 P.1 RanGAP TK, DHFR ON PCNA, H2A, etc. FdsL DBE Apaoptosis TRAIL 1.4 pRb (Retinoblastoma Protein) The retinoblastoma protein is a tumor suppression protein that is dysfunctional in many types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. It is also a recruiter of several chromatin remodelling enzymes Such as methylases and acetylases. i. Activation and Inactivation of pRb: In the hypophosphorylated state, pRb is active and caries out its role as tumor suppressor by inhibiting cell cycle progression. Phosphorylation inactivates pRb, during the M-to-G1 transition; pRb is progress ively dephosphorylated by PP1, returning to its growth- suppressive hypophosphorylated state. The ability of Rb to inhibit cellular proliferation is counterbalanced by the action of cyclin- dependent kinases (Cdks). In response to proliferative signals, Cdks are activated by their cyclin regulatory subunits to phosphorylate RB and thereby inactivate its protein binding function. Specifically, when quiescent cells are slimulated to enter the cell cycle, Cdk4/6-cyclin D complexes become active in mid-G1 and initiate the phosphorylation of Rb. Later in G1, Rb becomes hyperphosphorylated through the combined actions of Cdk4-cyclin D, Cdk2- cyclin E, and Cdk2-cyclin A.