Phases of the Cell Cycle

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Presentation transcript:

Phases of the Cell Cycle Prophase Metaphase Anaphase Telophase

Cell Cycle Progression: Requirements G2-M Cell Division G1-S

Cell Cycle Control Requirements: Cyclin:Cdk Complex Activated Protein Kinase

Expression Levels of Cyclins Oscillate

Various cell cycle phase-Cdks and Cyclins

Cdk Activation and Inactivation M-Cdk CAK (Cdk Activating Kinase)

Cdks can be inhibited while in a complex with a Cyclin Cyclin Dependent Kinase Inhibitor (CKI)

Control of Cyclin levels During the Cell Cycle Consequences: Decrease M-Cyclin, inactivate M-Cdk, and allow cytokinesis (cell division) to proceed.

Control of CKI (p27, p21, p16) levels During the Cell Cycle Consequences: Decrease CKI, increase Cdk/Cyclin Activity, and allow cell cycle progression.

Cell Cycle Checkpoints On Off Off Off On/Off Switches

On/Off Switches On Off On Off Off Off Off On On On On

Control of Chromosome Duplication Helicases

Activation of M-Cdk

The M to G1 Transition is Regulated by Stable Inhibition of M-Cdk

Guanine Exchange Factor Mechanism of MAPK (ERK) activation and cell proliferation. (Favorable Environment) Ras-Small GTPase Adaptor GDP PY YP GTP Guanine Exchange Factor (GEF) Transcription Factors Cell Cycle Genes are turned on/off (i.e. G1/S-Cyclins and S-Cyclins)

Mechanisms of ERK1/2-mediated cell growth (Due to a Mutation in Ras/Raf) Cell Death Cell Cycle Progression Cell Cycle Inhibitors i.e. CDKI: p27

ERK1/2-mediated cell growth Favorable Environment Cell Cycle Inhibitors i.e. CKI: p27 Cell Cycle Arrest Mechanism of ERK1/2-mediated cell growth Unphosphorylated Stable FOXO3a phosphorylated Degraded ERK1/2 FOXO3a CKI (p27) CdK/Cyclin Favorable Environment (Growth Factors!)

Regulation of Cell Death (Apoptosis) Anti-Apoptotic Pro-Apoptotic Unphosphorylated BAD and BIM Apoptosis Phosphorylated P-BAD and P-BIM Sequestered (BAD) or Degraded (BIM) Cell Cycle Progression

Mechanism of ERK1/2-mediated cell cycle progression Cell Death Mechanism of ERK1/2-mediated cell cycle progression Sequestered away from Bcl-2, Mcl-1, Bcl-XL P-BIM is polyubiquitinylated and degraded by the Proteasome Favorable Environment (Growth Factors!)

Review: Favorable Environments for G1 Entry Mitogens: Growth Factors such EGF, insulin, HRG, etc Receptor Tyrosine Kinase (RTK, i.e. EGFR) Mitogen Activated Protein Kinases (MAPKs. i.e. ERK) Transcription Factors (i.e. AP-1) Other Transcription Factors (i.e. Myc) Cyclins (G1 Cyclin)

Regulation of G1 to S Phase Transition G1-Cyclin

DNA Damage and Cell Cycle Arrest in G1 UV or Chemotherapy E3 Ligase (gene name = WAF1)

CKI The Activation of p21 (CKI) by p53 results in inactivation of G1/S-Cdk Complex. Consequence G1/S Cell Cycle Arrest CKI

The Mechanism by which p53 Arrests Cells in G1/S Phase DNA Damage (radiation or chemotherapy) p53 Cell Death (Apoptosis) Waf1 gene encodes the p21 protein (CKI) On p21 Protein Rb E2F P-Rb G1/S-Cdks G1/S-Cyclins DNA DNA is not repaired CKI

Cell Cycle Arrest or Apoptosis Caused by Excessive Mitogenic Stimulation