(From Dr. Savant’s Lecture, 27 June 2000 , by Brian Buschman)
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The p53 gene is the most commonly altered gene in human cancers. The p53 gene is one of the altered genes in half of all cancers.
The p3 genes is responsible for playing molecular policeman. If it senses that a gene is altered it will either repair the DNA or induce apoptosis. In the meantime it also causes translation of Waf-1 which binds to CDKs to prevent the cell from going past the G1 checkpoint until repairs have been completed.
There are different methods which induce cells to re-enter the G1 phase from Go allowing them to re-enter the S-phase. These signals include:
1) Cell-cycle contact which is a form of control from cell to cell which inhibits cell growth.
2) Cell-matrix contact which positively regulates cell growth based on interactions with the ECM.
3) Polypeptide growth factors are extracellular agents which usually stimulate cell growth. They usually act locally and bind to PM receptors. Most receptors are tyrosine-specific protein kinases which stimulate phospholipase-C to make IP3 and DAG which induce a Ca2+ influx. This causes the activation of the regulatory genes. The regulatory genes then lead to transcription of early and late response genes.
Polypeptide growth factors include:
a. Nerve growth factor (NGF)
b. Platelet derived growth factor (PDGF)
c. Epidermal growth factor (EGF)
d. Fibroblast growth factor (FGF)
e. Insulin-like growth factor (IGF-1)
f. Erythropoietin
g. Transforming growth factor-a which is needed for growth of epithelial cells.
Some growth factor receptors are G-protein receptors that activate RAS which when bound to GTP activates effectors. One such pathway involves RAS activating Ser/Thr kinases. Phosphorylated ser and thr activate dual-specificity kinases which leads to the production of MAP kinases which leads to production of transcription factors.
Antigen stimulation of t-cells is similar to mitogenic stimulation. When the antigen binds the receptor it sets off a cascade of kinases started by tyr phosphorylation.
After phosphorylation of tyr in the cytoplasmic receptor domains ZAP-70 finds and binds to two adjacent phosphorylated tyr residues. This functions to phosphorylate other substrates.
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