BCOR 103 1st Edition Lecture 19Outline of Last Lecture I. ApoptosisII. CaspasesIII. Intrinsic and Extrinsic PathwaysIV. Cell CycleOutline of Current Lecture I. CDK Regulation: Phosphorylation/DephosphorylationII. Transition Points in Cell CycleIII. Rb Phosphorylation Defines Restriction PointIV. CDK Activation and Inhibition Regulates G1-S TransitionCurrent Lecture- CDK Regulation: Phosphorylation/Dephosphorylationo CDK-activating kinases (CAK)o CDK-inactivating kinase (Wee1) Phosphates inhibit ATP bindingo Cdc25 phosphatase- CDK Regulation: CDK Inhibitors (CKIs)o CKIs can be phosphorylated and them degraded, thereby releasing inhibiton- Checkpoints and Transit through Cell Cycleo There are multiple checkpoints during cell cycleo Several monitor DNA integrity (replication defects or delays, mutations) and mitotic spindle formation- P53- Inactivating Mutations in ~50% of Human Cancerso P53 mutations lead to uncontrolled cell division of cells that contain damaged DNAo Damaged cells are also not removed by apoptosis in p53 mutantso Most p53 mutations from cancer patients are found in DNA-binding domainsThese 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 Cycleo Cells must monitor environment, nutrients, DNA integrity at each transition pointo Each transition is regulated by different set of CDKs- Transcription Factor Cascade Controls G0-G1 Transitiono Early response gene expression requires MAPKs, but no new protein synthesiso Early response gene regulate expression of delayed response geneo Cyclin D expression is regulated by multiple transcription factors- Regulation of the G1-S Transitiono Primary control point for yeast and animal cellso Cells sense nutrients, growth factors, cell size, etc. to determine if they can undergo cell divisiono START (yeast) RESTRICTION POINT (animals cells): decision point in late G1- CDK 4,6/Cyclin D Phosphorylates Rb, thereby Activating E2Fo E2F: transcription activator that binds to DNAo Rb: transcription inhibitor Binds to E2F, inhibiting its functiono CDK 4,6/Cyclin D Phosphorylates Rb, releasing E2F from inhibition - Rb Phosphorylation Defines Restriction Pointo Rb phosphorylation by CDK 4,6/Cyclin D represents restriction point in animal cellso CDK 4,6/Cyclin D activity is regulated by p53/p21 (CKI) pathway- CDK Activation and Inhibition Regulates G1-S Transitiono G1-phase CDKs must be activated prior to START and inactivated upon transit through STARTo S-phase CDKs must be inhibited prior to START and activated upon transit trough START- S-phase CDKs are Regulated by CKIso CKI (e.g. p27) binding inhibits S-phase CDK activity in G1 phaseo Phosphorylation of CKI by G1-phase CDKs leads to ubiquitin mediated proteolysisof CKIo Relieves inhibition of S-phase CDK activityo Induces entry into S-phase and DNA replication
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