Cell Cycle Flashcards
Labile tissue cells
These cells cycle continuously through the cell cycleClinical correlation: these cells are the first affected by total body radiation.
Stable cells
These cells are quiescent but can enter the cell cycle.Clinical correlation: If the ECM is intact, these cells can regenerate after injury.
Permanent cells
These cells have lost the capacity to proliferate.Clinical correlation: Examples are neurons and cardiac myocytes, which cannot be regenerated after they are lost. The brain responds by reprogramming cells, and the heart responds with hypertrophy. These are compensatory mechanisms.
Cyclin and CDK pairs that regulate the G1-S transition
Cyclin D - CDK4Cyclin D - CDK6Cyclin E - CDK2Accomplish the task by phosphorylating Rb protein
Relationship between cyclins and CDKs
CDKs can phosphorylate protein substrates when associated with a cyclin.Increased levels of cyclin increases activity of CDK.As CDK finishes phosphorylating, cyclin degrades, ending their partnership, and therefore, CDK’s phosphorylation of proteins.
Cyclin and CDK pairs that regulated the S phase
Cyclin A - CDK2Cyclin A - CDK1
Cyclin and CDK pair that regulates the G2 - M transition
Cyclin B - CDK1
G1-S checkpoint
Monitors the integrity of DNA before irreversibly committing cellular resources to DNA replication.
G2-M checkpoint
Ensures that there has been accurate genetic replication before the cell actually divides.
What molecule enforces the cell cycle checkpoints? How?
CDK inhibitors (CDKIs) enforce checkpoints vis modulating the CDK-cyclin complex activity.
CDKIs
Family One: p21, p27, and p57These inhibit multiple CDKsFamily Two: p15, p16, p18, and p19These have selective effects on CDK4 and CDK6.
Warburg Effect
One of the processes carried out to activate events necessary for cell growth (membranes and the like needed for new daughter cells)Marked by increased cellular uptake of glucose and glutamine, increased glycolysis, and decreased oxidative-phosphorylation.Clinical correlation: PET scans pick up tumor cells thanks to the Warburg Effect.
Receptor-mediated signaling
Ligands bind their receptors and initiate a cascade of intracellular events that culminate in a cellular response.
Intracellular receptos
Transcription factors that are activated by lipid-soluble ligands that cross the plasma membrane.
Cell surface receptor actions after ligand-binding
1) Open ion channels2) Activate an associated GTP-binding regulatory protein3) Activate an endogenous or associated enzyme, like a tyrosine kinase4) Trigger a proteolytic event or a change in protein binding or stability that activates a latent transcription factor. Numbers 2 and 3 are used for cell proliferation.
What does an active vs inactive Ras look like?What happens if there are mutations in Ras?
Active Ras has GTP bound, and inactive Ras has GDP bound. If the mutation leads to delayed GTP hydrolysis, augmented signaling results.
What’s the deal with tyrosine kinase kinases and tyrosine kinase inhibitors?
Tyrosine kinases play a role in many cancers, and tyrosine kinase inhibitors are important for the treatment of cancer. They are taken orally.Imatnib: myelogenous leukemiaErlotnib: lung cancerSunitnib: kidney cancer
G-protein coupled receptorClinical significance
After a ligand binds, the receptor associates with an intracellular GTP-binding protein that has GDP. Upon interaction with the receptor, the GTP-binding protein can exchange its GDP for a GTP.Malignant cells hijack normal GPCRs to survive, proliferate autonomously, evade immune system, increase their blood supply, and invade surrounding tissues/disseminate to other organs.
Wnt/Frizzled pathwayClinical significance
The Wnt pathway regulates intracellular levels of B-catenin, which is typically targeted for ubiquitin-directed proteasome degradation.If Wnt binds Frizzled, then Disheveled joins the party and disrupts the degradation-targeting complex. B-catenin can now move to the nucleus and form a transcriptional complex that has high potential to lead to colon cancer.
Why are adaptor proteins important?
Turns out phosphorylation/signaling of a molecule can lead to a variety of outcomes (as opposed to the previously taught linear design of signaling). Adaptor proteins help organize intracellular signaling pathways by linking different enzymes and promoting the assembly of complexes.
Transcription factors that regulate the expression of growth genes
MYC and JUN
Transcription Factor Facts
1) Most signal transduction ultimately influences cellular function through modulation of gene transcription via transcription factors2) TFs have a design that allows both interaction with DNA and other molecules (like RNA)3) DNA-binding domain on TF allows it to bind to enhancers, which are typically near genes4) To induce transcription, TFs must also have domains that can recruit histone-modifying enzymes, chromatin remodeling complexes, and RNA polymerase.
Growth factor activity
1) Mediated through binding to specific receptors2) Ultimately influence the expression of genes that promote entry of cells into the cell cycle, unblock cell cycle progression, prevent apoptosis, and enhance biosynthesis of components needed for growth and division. 3) If activity is dis-regulated or signaling pathways are altered, uncontrolled proliferation can result. 4) Many growth factor pathway genes are proto-oncogenes
Proto-oncogenes
If these genes undergo a gain-of-function mutation, they will be converted to oncogenes capable of driving unfettered cell proliferation and tumor formation. There are several areas where this mutation could have an effect:1) Coding sequence (a hyper-active protein made in NORMAL amounts)2) Gene amplification (normal protein OVER-PRODUCED)3) Chromosome rearrangement (a regulatory DNA sequence causes a normal protein to be OVER-PRODUCED; or, a fusion protein is either OVER-PRODUCED or is HYPERACTIVE.
Epidermal Growth Factor Receptor Family
1) These receptors have intrinsic tyrosine kinase activity2) Best-known is EGFR1 (AKA: ERB-B1 & EGFR) => mutations/amplification causes cancer3) ERBB2 receptor (AKA: HER2) => over-expression can lead to breast cancer4) Many of these receptors have been successfully targeted by antibodies.
Properties by which we define cancers
1) They reproduce in defiance of the normal restraints on cell division (both benign and malignant tumors)2) They invade and colonize territories normally reserved for other cells (malignant tumors only)
Clonal Evolution of Cancer
1) A cell does not become cancerous with just one mutation; several rounds of mutation and selection occur before a cell is cancerous2) A mutation gives an individual cell a growth advantage over surrounding cells3) The cancer can progress due to additional advantageous mutations.
Benign Tumor
Normal gland tubules that get rolled into a ball surrounded by a fibrous connective-tissue capsule.
Malignant Tumor
Fucked up cells without a fibrous cap
How can we make a normal cell cancerous?
1) Loss of normal regulation of cell proliferation, such as elimination of density-dependent contact inhibition)2) Avoidance of apoptosis3) Genetic instability4) Can escape from proper site5) Can survive/proliferate in distant sites (we call this “metastasis”)
Oncogenes
1) Made from proto-oncogenes when the proto-oncogene gets a gain-of-function mutation2) These are cells that act in a dominant fashion to stimulate or sustain replication3) These genes drive autonomous cell growth in cancer cells
Tumor-suppressor genes
2) These are cells that act in recessive fashion to increase/sustain proliferation OR decrease DNA repair.They are critical in the development of cancer: One good tumor suppressor gene is enough to control cancer, so two LOSS-OF-FUNCTION mutations are required (one in each chromosome copy) to cause failure of the protective nature of these genes. Two mutations = neoplasm.
Tumor-Suppressor Genes: Gatekeepers
Negative regulators that directly regulate cell growthRb, p53, APC, p19, Arf, p16, Ink4
Rb
Gatekeeper of tumor suppressor genes
p53
Gatekeeper of tumor suppressor genes
APC (Adenomatous polyposis coli gene)
Gatekeeper of tumor suppressor genes
p19
Gatekeeper of tumor suppressor genes
Arf
Gatekeeper of tumor suppressor genes
p16
Gatekeeper of tumor suppressor genes
Ink4
Gatekeeper of tumor suppressor genes
Tumor-Suppressor Genes: Caretakers
These genes are involved in repairing DNA damage or maintaining genomic integrityATM, Brca1, Brca2, MIh1, Msh2
ATM
Caretaker of tumor suppressor genes
Brca1 and 2
Caretaker of tumor suppressor genes
MIh1
Caretaker of tumor suppressor genes
Msh2
Caretaker of tumor suppressor genes
Patterns of metastatic spread
Lymphatic: typical of carcinomasHematogenous (to lung or liver): typical of sarcomasSeeding (of body cavities or surfaces): typical of ovarian carcinoma
