BCOR 103 1st Edition Lecture 19 Outline of Last Lecture I Apoptosis II Caspases III Intrinsic and Extrinsic Pathways IV Cell Cycle Outline of Current Lecture I CDK Regulation Phosphorylation Dephosphorylation II Transition Points in Cell Cycle III Rb Phosphorylation Defines Restriction Point IV CDK Activation and Inhibition Regulates G1 S Transition Current Lecture CDK Regulation Phosphorylation Dephosphorylation o CDK activating kinases CAK o CDK inactivating kinase Wee1 Phosphates inhibit ATP binding o Cdc25 phosphatase CDK Regulation CDK Inhibitors CKIs o CKIs can be phosphorylated and them degraded thereby releasing inhibiton Checkpoints and Transit through Cell Cycle o There are multiple checkpoints during cell cycle o Several monitor DNA integrity replication defects or delays mutations and mitotic spindle formation P53 Inactivating Mutations in 50 of Human Cancers o P53 mutations lead to uncontrolled cell division of cells that contain damaged DNA o Damaged cells are also not removed by apoptosis in p53 mutants o Most p53 mutations from cancer patients are found in DNA binding domains These notes represent a detailed interpretation of the professor s lecture GradeBuddy is best used as a supplement to your own notes not as a substitute Three Major Transition Points in Cell Cycle o Cells must monitor environment nutrients DNA integrity at each transition point o Each transition is regulated by different set of CDKs Transcription Factor Cascade Controls G0 G1 Transition o Early response gene expression requires MAPKs but no new protein synthesis o Early response gene regulate expression of delayed response gene o Cyclin D expression is regulated by multiple transcription factors Regulation of the G1 S Transition o Primary control point for yeast and animal cells o Cells sense nutrients growth factors cell size etc to determine if they can undergo cell division o START yeast RESTRICTION POINT animals cells decision point in late G1 CDK 4 6 Cyclin D Phosphorylates Rb thereby Activating E2F o E2F transcription activator that binds to DNA o Rb transcription inhibitor Binds to E2F inhibiting its function o CDK 4 6 Cyclin D Phosphorylates Rb releasing E2F from inhibition Rb Phosphorylation Defines Restriction Point o Rb phosphorylation by CDK 4 6 Cyclin D represents restriction point in animal cells o CDK 4 6 Cyclin D activity is regulated by p53 p21 CKI pathway CDK Activation and Inhibition Regulates G1 S Transition o G1 phase CDKs must be activated prior to START and inactivated upon transit through START o S phase CDKs must be inhibited prior to START and activated upon transit trough START S phase CDKs are Regulated by CKIs o CKI e g p27 binding inhibits S phase CDK activity in G1 phase o Phosphorylation of CKI by G1 phase CDKs leads to ubiquitin mediated proteolysis of CKI o Relieves inhibition of S phase CDK activity o Induces entry into S phase and DNA replication initiation
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