TAILIEUCHUNG - Chapter 080. Cancer Cell Biology and Angiogenesis (Part 8)

PI3K is a heterodimeric lipid kinase that catalyses the conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol trisphosphate (PIP3), which acts as a plasma membrane docking site for proteins that contain a pleckstrin homology (PH) domain. These include the serine/threonine kinases Akt and PDK1 that are key downstream effectors of PI3K action (Fig. 80-2). The PI3K pathway is activated in 30–40% of human cancers and is thought to play a critical role in tumor cell survival, proliferation, growth, and glucose utilization. Amplification or activating point mutation of the gene encoding the catalytic subunit of PI3K (p110) is observed in 20–30%. | Chapter 080. Cancer Cell Biology and Angiogenesis Part 8 PI3K is a heterodimeric lipid kinase that catalyses the conversion of phosphatidylinositol bisphosphate PIP2 to phosphatidylinositol trisphosphate PIP3 which acts as a plasma membrane docking site for proteins that contain a pleckstrin homology PH domain. These include the serine threonine kinases Akt and PDK1 that are key downstream effectors of PI3K action Fig. 80-2 . The PI3K pathway is activated in 30-40 of human cancers and is thought to play a critical role in tumor cell survival proliferation growth and glucose utilization. Amplification or activating point mutation of the gene encoding the catalytic subunit of PI3K p110 is observed in 20-30 of breast colon brain gastric and ovarian cancers and amplification of the Akt2 gene occurs in breast ovarian and pancreatic cancers. The tumor suppressor PTEN phosphatase with tensin homology a lipid phosphatase that acts as an off signal for PI3K by dephosphorylating PIP3 is mutated in many human cancers leading to unchecked activity of the PI3K pathway. Akt promotes cell survival by activation of the transcription factor nuclear factor of kB NFkB it also enhances cell cycle progression by inhibition of glycogen synthetase kinase 30 GSK30 and FOXO transcription factors thus preventing inactivation of Myc 0-catenin cyclin D1 and cyclin E and blocking upregulation of p27Kip1 and Bim an apoptosis-inducing protein . Furthermore the growth of cancer cells requires the activation of two downstream kinases mammalian target of rapamycin mTOR and p70S6K whose activities promote the translation of cellular mRNAs. Targeted interruption of the PI3K pathway is being attempted at multiple levels. Inhibitors of mTOR including rapamycin and its more soluble ester derivative temsirolimus tem selectively kill human tumor cell lines with PTEN mutations and upregulated PI3K pathway activity. Early clinical data indicate that tem has activity in renal cell cancer perhaps by blocking

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