Day 3, Lecture 2 (Aug 24): Biology of Cells II- Cell Cycle/Differentiation Molecular and Cellular Systems Flashcards
Destroying Angel
- Amatoxin:
- Thermostable, rapid absorption, irreversible damage to liver and kidney
- Perforate plasma membranes causing organelle leakage. Also inhibits RNA polymerase II/III (stops protein synthesis). Cells die, liver dissolves
- symptoms: coughing, headache, shortness of breath, vomiting, cramps, diarrhea, delirum, convulsions, death
Cirrhosis
- Long term liver damage causing cell death and scarring
- causes:
- Alcohol, Hepatitis (B or C), non-alcoholic fatty liver disease
- Symptoms
- Tired, itchy, leg swelling, jaundice, ascites
- Leads to:
- hepatic encephalopathy (confusion/coma), bleeding, liver cancer, death
What three concepts underlie the unity of life
- Cell theory
- A cell is the fundamental unit of organismal structure/function
- all cells come from cells
- Cells maintain/transfer hereditary information determining fate
- Bioenergetics (energy flow and transformation)
- cell metabolism converts nutrients into energy to do work
- Evolution
Degrees of organization
- Organs/structures formed from tissues
- Tissues from cells
- Cells of organelles
- Organelles from molecules
- Molecules from atoms
What are the four fates of cells
- Survival
- Division
- Differentiate
- Die (apotosis or necrosis)
Liver cell types
- Hepatocytes
- Glycolysis, gluconeogenesis, produce bile
- Kupffer cells
- macrophages protect from pathogens and cancer cells
- Stellate cells
- Store Vitamin A
- Sinusoidal Cells
- Endothelial Cells lining sinuses (space between hepatocytes). Regulate Molecule passage
The ___ is the smallest fundamental replicating unit
Cell
Cells organize into ___ and adopt specific fates
tissues
Cell fate determined by
- communication with other cells, microenvironment
- Receiving, transmitting,interpreting multiple signals
- self evaluation
- Alters cell cycle, gene expression, cytoskeleton, etc.
Disrupted cell fate decisions underlie ____, ____, and _____ malfunctions (e.g. poisoning and cirrhosis)
Cellular, tissue, and organ
Tuberous Sclerosis
- Rare (1/8000) multi-system genetic disease.
- Symptoms
- benign tumors, seizures, intellectual disability, skin abnormalities, lung/kidney disease
- Inappropriate cell proliferation forming hamartia (malformed tissue), hamartomas (benign growths like facial angiofibroma)
- Mutational loss of both TSC1/2 alleles prevents tumor suppressing function; ie Knudson “two hit” hypothesis
- Sporadic:
- 2 acquired mutations
- Hereditary:
- 1 inherited, 1 acquired mutation
- Sporadic:
Familial Adenomatous Polyposis
- Genetic disease benign polyps in large intestine epithelium. Blood in stool, anemia (iron loss). Malignant transformation into colon cancer if untreated
- Mutation (1 or 2 hit) of adenomatous polyposis coli (APC), a tumor suppressor gene regulating ß-catenin
- ß-catenin regulates cell-cell adhesion and gene transcription controlling proliferation
- further mutations (e.g. in p53 or kRAS) to APC-mutated cells lead to cancer
Stroke
Myocardial Infarction (heart attack)
Cell cycle progression controlled by highly regulated ____
CDKs
Differentiation, senescence, and apoptosis all require ordered cell cycle exit to G0 before Restriction point
Extracellular signals target cell cycle machinery to
communicate cell fate
_____ is a key period for making cell fate decisions
Restriciton point
do multiple signaling inputs (positive and negative) converge on the Restriction point to determine cell fate
yes
The Restriction point
Signals activate G1 CDKs to continue the cell cycle and become mitogen independent or inhibit CDKs to ____
- exit and adopt an alternative fate
Adipogenesis
Adipogenesis promotes _____
- G1 progession
- Excess calories/adipocyte size activate growth factors, adipogenesis in pre-adipocytes (undifferentiated fibroblasts)
- Signal transduction activates G1 components driving R point progression
Mitogenic control of cyclin D-CDK4
- Cyclins and CKDs have to be brought together and then phosphorylated to become active
G1 progression and the switch to mitogen independence
- Mitogens bind to the cell-surface receptors to initiate intracellular signaling pathways.
- ex. A small GTPase Ras will activate MAP kinase cascade, leading to increased expression of numerous immediate early genes, including the gene encoding the transcription regulatory protein Myc. Myc increases the expression of many delayed-response genes, including some that lead to increased G1-Cdk activity (cyclin D-Cdk4), which triggers the phosphorylation of members of the Rb family. This inactivates the Rb proteins, freeing gene regulatory protein E2F to activate the transcription of G1/S genes including the including G1/S cyclin (Cyclin E) and S-cyclin (Cyclin A). Cyclin E has a positive feedback on phosporylation of Rb thus pushing the cell cycle forward.
What are Mitogens
- Extracellular signal molecules that stimulate cell division, primarily by triggering a wave of G1/S-Cdk activity that relieves intracellular negative controls that otherwise block progress through the cell cyle
*
Cell fate decisions are made at the
- Restriction point
- Extracellular signals target cell cycle machinery controlling the Restriction point to make appropriate cell fate decisions
Growth factors initiate positive feedback loop of
G1 cell cycle machinery driving Restriction point progression and growth factor independence
Disrupted Restriction point control compromises cell fate decisions. Give examples
Obesity and B-cell loss in type II diabetes
What are the three major Checkpoints in the cell cycle
DNA Damage response
What is p53
- The guardian of the genome
- Tumor suppressor protein regulating transcription to prevent genome corruption
Mechanism of Progeria (Hutchinson-Gilford Progeria Syndrome)
- Lamin A mutation prevents farnesyl group removal
- Lamin remains attached to nuclear rim and cannot form nuclear lamina to support nuclear envelope
- Prevents chromatin organization during mitosis, so cell division inhibited
Mechanism of Ataxia Telangiectasia (ATM)
- Serine/threonine protein kinase recruited and activated by DNA damage (esp. Double-strand breaks)
- Phosphorylates key proteins activating DNA damage checkpoint
- Leads to cell cycle arrest, DNA repair or apoptosis
