5
Onko (Subject) / 5. Fava (Lesson)
- Describe the various mechanisms that contribute to the regulation of CDK activity von Wiki: cyclin binding:The structure of human Cdk2 revealed that CDKs have a modified ATP-binding site that can be regulated by cyclin binding. Without cyclin, a flexible loop called the activation loop or T-loop blocks the cleft, and the position of several key amino acid residues is not optimal for ATP-binding. With cyclin, two alpha helices change position to permit ATP binding.Phosphorylation: Full kinase activity requires an activating phosphorylation on a threonine adjacent to the active site. Unlike activating phosphorylation, CDK inhibitory phosphorylation is vital for regulation of the cell cycle.CDK Inhibitors: A cyclin-dependent kinase inhibitor (CKI) is a protein that interacts with a cyclin-CDK complex to block kinase activity, usually during G1 or in response to signals from the environment or from damaged DNA.Suk1 or Cks: The CDKs directly involved in the regulation of the cell cycle associate with small, 9- to 13-kiloDalton proteins called Suk1 or Cks. These proteins are required for CDK function, but their precise role is unknown.
- Describe the molecular events that define commitment to the cell cycle (START) Cell cycle clock: Decision if G0 or cell cycle depends on a variety of signals EZ matrix, hormones etc. Restriction point: Hyperphosphorylation of Rb initiates cell proliferation SCF inhibits p27 → CDK activation Sister chromatid cohesion is established in S-Phase after Cdk activation.
- What drives cells into mitosis and how is the transition regulated? CDK1/M-Cyclin activation switch: Cdk1/m-cyclin are inactivated by wee1. CDC25 phosphorylates the CDK1/M-cycline complex resulting in a positive feedback loop → more CDC25 activation/less CDK-1/M-cyclin inhibition.
- What drives the cells out of mitosis and how is the transition regulated? APC/C and SCF initiate a drop in CDK activity (ubiquitinylates cyclin B) and ubiquitinylate securin, activating separase after spindle assembly checkpoint → initiates anaphase → spindle pulls sister chromatids apart.
- Which are the possible causes and consequences of cell senescence (what is the senescent phenotype)? Which proteins are responsible for this process? Definition: Cellular aging / replicative senescence Phenotype: Growth arrest, apoptosis resistance + altered gene expression. Tumour suppressive mechanism (benefitial), loss of regenerative capacity (detrimental) Cause: Main cause: Telomeres are shortened = ageing. Mitotic cells can undergo senescence upon stress. G0 is reversible, Senescence widely irreversible. Responsible proteins: Growth arrest: G1: dominant p27 expression (cell cycle inhibitor). G2 arrest: under presence of const. active Ras ( Tumor cells can also undergo senescence after chemo p53: Cells enter senescence after p21 and p27 activation by p53. Also: Bcl-2, BCL-X + MCL1 expression increase likeliness of senescence. p16 present in senescent cells (not all) → No exclusive Senescence marker.
Advertisement