Slide1: The Cell Cycle The period extends from cell existence to time of its division.


Slide2: Cell Cycle Characteristics Temporally ordered events Irreversibility Oscillations Checkpoints


Slide4: Length of interphase can vary depending on cell type: <30 minutes in early embryo 12-36 hours for rapidly dividing human cells (e.g. blood) Months for slow growing cells (e.g. liver)


Cell Cycle regulation: Cell Cycle regulation Growth factors & Cyclins Anchorage dependence Density-dependent inhibition


Slide7: G1  D S E & A M A & B G1  CDK4 S  CDK2 M  CDK1 p16 p 21


Slide8: Retinoblastoma Protein (Rb) = an important cell cycle regulator and tumor suppressor that is controlled by how much it is phosphorylated. It is a SUBSTRATE for the enzyme cyclin-dependent KINASE.


Transcription Factor E2F : Transcription Factor E2F Transcription Factor: a protein that helps TRANSCRIBE genes (DNA  RNA) E2F is a transcription factor that is responsible for helping transcription of genes that help cells enter S phase E2F S-phase Gene Pretend this is a gene (piece of DNA) that needs to be transcribed to help push cells into S phase; without the transcription factor, E2F, it is NOT transcribed (no mRNA is made). S-phase Gene When E2F is allowed to “sit” on the gene, it helps the gene to undergo transcription. Copies of mRNA are made Copies of mRNA Transcription


Rb and cdk’s: Rb and cdk’s No Transcription; No continuation through the cell cycle S-phase genes transcribed! Start S-phase! Mitosis Promoting Factor


Cdk inhibitors (CIP)= (CKI): Cdk inhibitors (CIP)= (CKI) p21 and p16 are proteins that inhibit the function of cdk’s. They inhibit cdk function, Rb in turn DOES NOT get hyperphosphorylated and E2F is NOT able to transcribe genes, and the cell cycle is stopped!


Restriction Point: Restriction Point Restriction point is found at the end of G1. The cells must be checked for two things: 1) cell size- the cell must be big enough to start synthesis of DNA 2) no damage in the genetic material; if DNA is damaged, the cell will not progress to S phase. In cancer cells, this restriction point is often abnormal, allowing damaged DNA to be replicated and passed to daughter cells. This is how mutations get from one cell to the next. If it is a mutation in a gene that normally controls growth, then the cell will not have normal regulation of growth.


CELL CYCLE CHECKPOINTS: CELL CYCLE CHECKPOINTS G1 S G2 M CYCLIN B/ cdc2 CYCLIN A/ cdk2 CYCLIN E / cdk2 CYCLIN D / cdk4,5,6


CELL CYCLE CHECKPOINTS: CELL CYCLE CHECKPOINTS MITOSIS ENTRY (G2/M) Replication Complete Growth/ Protein Synthesis adequate No DNA Damage S-PHASE ENTRY (G1/S) Mitosis Complete ?signal - cyclin degradation Growth/ Protein Synthesis (G1 CYCLINS) No DNA Damage OTHERS MITOSIS EXIT: ?coupling to S-phase S PHASE : coupling to mitosis also in response to DNA damage G1 sequence of events signaling from cell surface


Slide17: Cell Cycle Checkpoints Two major checkpoints function in mitosis, at entry into mitosis (G2/M checkpoint) at the metaphase to anaphase transition (metaphase checkpoint). The G2/M checkpoint functions as cells enter mitosis. It monitors microtubule-dependent events, such as separation of duplicated centrosomes at G2, and delays the G2/M transition in the presence of microtubule poisoners. Thus, this checkpoint determines the timing of mitotic entry and ensures a productive mitosis. The metaphase checkpoint monitors the attachment of the mitotic spindle to kinetochores and the tension generated by mitotic spindle attachment. In the presence of a single unattached kinetochore, the metaphase checkpoint halts the separation of sister chromatids and thereby provides additional time for spindle attachment. Thus, the metaphase checkpoint ensures a high fidelity of chromosome separation and prevents aneuploidy during mitosis


Why does it work this way? Because a number of things all have to be properly coordinated before mitosis starts.: Why does it work this way? Because a number of things all have to be properly coordinated before mitosis starts. G1 S G2 M - is DNA replicated - is the cell big enough ? - does it have enough stuff ? G0 MPF


MPF regulates one of several cell cycle checkpoints: MPF regulates one of several cell cycle checkpoints


cyclins and cyclin dependent kinases appear at different stages of the cell cycle: cyclins and cyclin dependent kinases appear at different stages of the cell cycle