BIOL1110 From Molecules to Cells Lecture 6 PDF

BIOL1110 From Molecules to Cells (Lecture 6) Cell cycle control Dr. Gary Ying Wai Chan Office: Rm4N11 KBSB Email: [email protected] Cell cycle Under optimal conditions (e.g., Nutrition, temperature, pH), the length of eukaryotic cell cycle is constant for a...

BIOL1110 From Molecules to Cells (Lecture 6) Cell cycle control Dr. Gary Ying Wai Chan Office: Rm4N11 KBSB Email: [email protected] Cell cycle Under optimal conditions (e.g., Nutrition, temperature, pH), the length of eukaryotic cell cycle is constant for any given cell type External condition is not favorable, the duration of cell cycle will be longer - Cells may delay progress through G1 or G2; or - Some may enter a specialized resting state (G0) before resuming G0 proliferation (quiescent) - Not all cells are dividing, some cell may enter G0 stage permanently (senescent and differentiated) What control cell cycle? How? - Cell cycle consists of hundreds of sequential events that must proceed in an orderly manner Effective control mechanisms are required Cell-cycle control system - Central components of cell-cycle control system: - Hartwell, Hunt, and Nurse won the 2001 Nobel Prize in Medicine for their discovery of these central molecules. http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/illpres/illpres.html Cyclin-dependent kinases (cdks) and cyclins - Cdks have kinase activity when cyclin is tightly bound - Cdk protein levels are almost constant throughout the cell cycle - Different cyclins are found in cells and their protein levels change cyclically  Different cyclin-cdk complexes trigger different cell-cycle events  The restriction point (R), also known as the Start, at which the cell becomes "committed" to the cell cycle (extracellular signals are no longer required to stimulate proliferation) Cyclin A/B-CDC2: G2/M cyclin-CDKs Clb1, Clb2, Clb3 and Clb4: G2/M cyclins Cyclin A-CDK2: S cyclin-CDK Clb5 and Clb6: S cyclins Cyclin E-CDK2: G1/S cyclin-CDK Cln1, Cln2 and Cln3: G1/S cyclins Cyclin D-CDK4/6: G1/S cyclin-CDKs Three checkpoints G1/S checkpoint: Upon receiving a pro- mitotic extracellular signal, G1 cyclin-CDK complexes (cyclin D- CDK4/6 in human cells) become active, promoting the expression of transcription factors (E2F) by inactivating RB G1/S protein (retinoblastoma checkpoint protein, an inhibitor of E2F). E2F promotes the expression of cyclin E and other enzymes P53p21 required for DNA replication. Activation of G1/S checkpoint block https:// transcription of cyclin E basicmedicalkey.com/ by inhibiting G1 cyclin-  DNA damage activates ATM/ATR G2/M checkpoint: ATM/ATR Mitotic cyclin-CDK complexes (cyclin A/B- CDK1 in human cells), which are synthesized but inactivated during S and G2 phases, promote the CHK2/ initiation of mitosis by CHK1 stimulating downstream Activation Inhibition proteins involved in chromosome condensation and mitotic spindle assembly. Damaged or unreplicated DNA activates G2/M checkpoint by inactivating CDK1 activity. ATM/ATR/CHK1/CHK2: kinases that are activated in response to DNA damage Adapted from Latif et al., 2001 (0.1100/tsw.2001.297) Wee1 phosphorylates and Metaphase-anaphase checkpoint (spindle assembly checkpoint): A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore (i.e., cohesin). APC also targets the mitotic cyclin (cyclin B in human cells) for degradation to allow anaphase onset. The mitotic checkpoint complex (MCC): Bub3- Lara-Gonzalez et al. 2012 Current Biology BubR1-Mad2-Cdc20 Securin inhibits What happens if cell-cycle control system goes wrong? Examples of downstream checkpoint genes -p53, a tumor suppressor, is activated if DNA is damaged to inhibit cell cycle progression by: 1) Cell cycle arrest 2) Activates enzymes to repair DNA 3) Programmed cell death - If genes that regulate cell growth are mutated, it can result in cancer. -Bishop and Vamus: Nobel These genes are therefore known prize in Medicine 1989. as proto-oncogenes Proto-oncogenes An oncogene is a gene that has the potential to cause cancer. A proto- oncogene is a normal gene that could become an oncogene due to mutations or increased expression. Three ways that proto-oncogene becomes oncogene: 1.A mutation occurs that increases the protein activity and loss of negative regulation Front. Mol. Neurosci., 21 May 2019 2. An increase in protein expression (e.g., MYCN gene) 3. Chromosomal translocation, in which the proto-oncogene relocates to a new site that leads to high expression, or the proto-oncogene fuses to other gene to create a new gene product, e.g., BCR gene in chromosome 22 fuses with a fragment of chromosome 9 that contains ABL1 gene, to create BCR-ABL1 gene that causes leukemia.  Question time! True or False Q: Both cyclin E-CDK2 and cyclin D-CDK4/6 phosphorylate RB protein. Q: In human cells, CDK2 can only bind to cyclin E. Q: p53 is inhibited by MDM2. Q: Cyclin E degradation is required for G1-S transition. Q: Spindle assembly checkpoint blocks cyclin B degradation. Q: Proto-oncogenes become oncogenes when certain tumor suppressors are mutated.