6.1 – The Cell Cycle and CancerCell Cycle: o Gap 1 – G1: growth and metabolism, duplication of organelleso If cell is not going to be duplicated, cell enters G0 Phaseo Cell cycle arresto Brain cells are usually here o Regulated re-entry into the cell cycle if it needs to divide o After G1, once organelles are duplicated = S-Phaseo DNA REPLICATIONo DNA polymerase is made, nucloetides needed o we can observe this phase by incorporation of radioactive nucleotides o Phase between S-Phase and Mitosis = G2 – Gap 2 - DNA reaches a maximum level of incorporation of nucleotides- Growth, preparation for mitosis- Checkpoint for errors in replication o Mitosis: chromosome segregation and cytokinesis (division into2 daughter cells)Apoptosis: a way out if something goes wrong in the cell cycle Programmed cell death (only cells with problems) = cellular suicide!  Only for multicellular organism thing, killing off the bad cell before it takes the rest of the tissue/organism with it Mitochondrial proteins will leak out, caspases will degrade the nucleus, cytoskeleton will collapse, genome will be degraded Regulation of Cell Cycle in Eukaryotic Organisms:1. Birth: rapidly forming cells2. Adulthood Necessary because the cell cycle allows multi-cell eukaryotes to create a body plan This regulation prevents growth and division at the wrong time, too rapid, too slow, failture to stop  Control System:o Timer: each event starts and ends at a specific timeo Mechanism to ensure correct sequence of eventso Mechanism to ensure each event happens once per cycleo On/off switches – triggered events must occur to completion andthen stopo Back Ups/ Redundancy – take over in case of system malfunctiono Adaptability – different rules for different cell types, response to environmental conditions How do cells know when to enter various stages of the cell cycle? Cdks (cyclin-dependent protein KINASES) – enzymes that initiate entry into the S or M phase of the cell cycle Phosphorylation on protein side chains can control: Protein’s enzyme activity Lifetime of a protein Protein-protein binding Subcellular location  Therefore: Cdks phosphorylate proteins necessary to bring about various events in the cell cycle  Cdks are inactive on their own!o They must bind a partner protein called a cyclin o Concentrations of cyclins rise and fall during the cell cycleo Cyclins are tightly regulated!o So: the activity of Cdks rises and falls during the cell cycle  Rb Phosphorylation: - Important part of taking the cell into S phase- It inhibits transcription factor (E2F inhibitor)- Rb is a substrate for Cdk - Cdk activation leads to Rb phosphorylation and dissociation from E2F- E2F is now free to promote transcription of genes encoding proteins necessary for cell cycle progression Early G1 Phase: low Cdk activityLate G1 Phase: rising Cdk activity Cdk Activity is controlled by cyclins… but what controls the cyclins?- Answer = controlled transcription and controlled protein degradation - Ubiquitin-Proteasome Degradation Pathway: Ubiquitin: 76 amino acid protein that is joined to specific lysin residues in proteins (Like phosphorylation, this is a post-translational modification) Poly-Ubiquitinated: proteins are targeted to proteasome where they are chewed up into short fragments  Ubiquitin is attached to E1, it is moved to E2, which binds to E3 E3 will bind to a substrate, which the ubiquitin is then moved to  When enough ubiquitins are attached, the substrate will go to proteasome Cyclins contain a specific “destruction box” amino acid sequence: Way to control activity of cdks Failure of Cell Cycle controls often leads to Cancer:  Hallmark of cancer = uncontrolled cell growth  Happens when Apoptosis cannot happen, can’t recognize bad cells As a result, cells can continue to develop further mutations and then there are enough mutations to have uncontrolled growth = it loses control! Common Properties of Cancer Cells: Cancer cells are most easily studied by culturing dissociated cancer cells Normal Cells:o Grow in a monolayero Need to adhere to petri dish Cancer Cells:o Grow in clumps (foci)o Lack contact inhibition – they no longer respond to signals that cause normal cells to stop growing and dividing (like depletion of growth factors, or contact with neighbors)o Anchorage-independent – cells are rounded and do not adhere to culture dish or each other o Can be grown in suspension (normal cells cannot) o Growth Factor-independent – growth occurs in absence of stimulatory factors since the cancer cell cycle no longer depends on interaction of such factors with surface receptors o Immortal – normal cells undergo only a limited number of divisions, regardless of growth conditions; cancer cells divide indefinitelyo Display chromosomal aberrations (aneuploidy) – including translocations, deletion of parts or entire chromosomes, and duplication of parts or entire chromosomesCauses of Cancer: Major contributors to cancer are environmental Benzopyrene: mutates bases in DNA, specifically guanine (found in coal tar, automobile exhaust, cigarette smoke, charbroiled meat) Viruses can carry genes whose products block growth-inhibiting functions of some cellular proteins or promote inappropriate re-entry into the cell cycle o HPV gene: alters function of tumor suppressor genes Genetics of Cancer:2 Classes of Genes Contribute to Genes1. Oncogenes are the accelerators of the cell cycle - Promote proliferations- Cause protooncogenes to be expressed at the wrong time2. Tumor-Suppressor Genes are the brakes of the cell cycle - Prevents proliferation - Cause loss of restraint on proliferation 6.2 – Signal Transduction & Oncogenes:What are proto-oncogenes and oncogenes?Oncogenes: mutant versions of proto-oncogenes (cellular genes) whose encoded proteins promote cell growth and division  Promote genetic instability  Allow cells to grow and divide despite signals saying don’t!Proto-oncogenes: the non-mutant version of oncogenes, they give rise to normal proteins  Preventing apoptosis of bad cells Promoting invasion of other tissues Cancer Development is a Multistep Process:- Normal cell  lesion  benign tumor  bad  worse - Activation of a single oncogene is rarely sufficient enough tocause cancer, this requires activation of multiple oncogenes and inactivation of tumor-suppressor genes How do