Cell Biology Flashcards
Cell
Cell birth and death rate regulates the adult body size.
Adult cells do not normally proliferate unless it is healing,
Cancer occurs due to excessive cell division.
driving force of a tumor is the dev. of (4-7) genetic mutations.
Cell division in Cancer
Occurs due to mutation in GF or proteins that regulate cell division and induces uncontrolled proliferation. The cell lose their mechanism to induce apoptosis.
Cell Cycle G1 phase
- “Gap” Prepares for DNA replication by:
1. Making proteins
2. Size of the cell
3. Nutrient check
Cell Cycle S phase
“Synthesis” DNA replication and centrosome duplication
1. starts with 2n 2c ends with 2n 4c
Cell Cycle G2 phase
“Gap” replication of chromatids, and preparation for mitosis.
Cell Cycle M phase
“mitosis” cell cycle produces 2 daughter cells.
prophase, metaphase, anaphase and telophase
Has 2 most important chpts.
Cell Cycle G0 phase
Non dividing resting differentiated state
Most human cells in G0 phase
Chekpoint G1/S
Triggers replication initiation.
DNA damage
Monitors DNA throughout cycle for damage
G2/M
Prevents entry into mitosis unless all chromosomes have completely replicated their DNA.
Spindle Assembly Checkpoint
Checkpoint within the M phase that prevents entry into anaphase unless replicated chromosomes are properly attached to a spindle.
Chromosome Segregation
Prevents exit from mitosis if chromosomes are not properly segregated.
Go ahead or Stop Signal
Activators or inhibitors usually proteins
- Go-ahead promote cell growth and division
- Can be internal/ cytoplasmic or external (growth factors)
- Primary mechanism of control is via phosphorylation or dephosphorylation of proteins.
Cyclins
- Expressed a specific points in cell cycle
- Proteins that control cell progression through cell cycle
- Activates cyclin dependent kinases (CKD)
- Cyclin-CDK complex trigger onset of key cycle progression and send secondary signals through cell via phosphorylation.
- Cyclins have to detach from complex and get degredated once cell cycle is done.
Cyclin-CDK complex
- Phosphorylates substrates to activate cell cycle specific events like initiating DNA replication
- Has to be inactivated to prevent multiple initiation events.
Degradation of cyclin proteins
Cyclins are ubquitinated to target them for degradation.
Ubiquitin is a small protein targeting the substrate for degradation via proteasome. different Ub molecules E1, E2, E# that activates, conjugates, and ligates.
Proteasome (26S)
Large protein in the cytoplasm and nucleus. It degrades damages proteins by proteolysis. Highly regulated has two 19S caps and a 20S catalytic core.
- 19S recognize UB proteins and transfer them to the 20S core (has to have the UB tag or it can’t enter)
- 20S this is the site where the proteins are degraded with trypsin (hydrolyze proteins) like actions.
Chromosome replication
3 functional elements required
- Replication origin: DNA polymerase and other proteins initiate protein synthesis.
- Centromere: contristed regions required for daughter chromosomes
- Telomeres: at end of chromosome to prevent info loss. after each cycle the telomere shortens. Used because the lagging strand cant synthesis the whole length of the DNA.
Senescence
Telomerase is not expressed in adults, Senescence is a telomeric shortage. When there is none left the replication stops.
Cancer cells induce telomerase functions that’s how we get uncontrolled cell division.
Checkpoints
-Halt cell cycle progression to ensure that crucial events are started prior to completion of prereqs
DNA damage Checkpoints
Ensure the fidelity of genetic info by arresting the cell cycle progression and facilitation DNA repair pathways.
- This checkpoint is in every phase. this is important because damages template and the dNTP shortage can impede proper genome duplication.
- ATM or ATR will activate P53 to inhibit Cyclin-CDK complex stop the cycle.
Cell growth
control mass of the organ and depends on
- cell mass: size of cell
- cell division: increase the number of cells
- cell death: decrease the number of cells
Growth factors
- extrinsic signals that control, drives and activate cell division.
- There are 3 classes: mitogenic, growth factors and survival factors
- Growth factors attach to receptor, tyrosine kinase sends signal, cell divides
Mitogenic factors
Stimulate cell division
Growth factors
Stimulate protein synthesis and membrane biogenesis
Survival factors
Inhibit cell death
Protooncognes
- Act in cell proliferation paths. Needs a ligand to bind and activate the EGFR and induce cell division.
- Most are kinases, small G proteins, and transcription factors, very controlled activity, Activating mutation will cause them to become oncogenes
Oncogenes
-Mutated protooncogenes resulting from a gain of function mutation
Mitogenic signaling pathways
-Extracellular proteins that stimulate cell division directly by controllinf the entry of cells into the cell cycle.
GEF
-Guanine exchange factors: removes GDP and adds GTP to the molecule (activate RAS and disassociate it from SOS)
GAP
GTP-ase activating protein that binds to active small G-proteins and activate the GTP-ase activity.
-GTP-ase activity is to inactivate G-protein.
GDI
Guanine disassociation inhibitor: binds to some GTP bound G protein and prevent their activation (but not RAS).
RAS pathways
control many different aspects of cell growth and proliferation
many downstream of RAs are protooncogenes
MAP Kinase
Activated by MEK to signal transcription factors that initiate cell cycle progression.
ERK
Activated by MEK to signal transcription factors, cell adhesion proteins and regulate cell growth,
Mitogenic transcription factors
FOS, JUN and MYC
Activate transcription of genes essential for cell cycle progression.
-AP1 : made from combination of Fos and Jun. This is a heterodimers that can influence cyclins, GF and tumor suppressors. This factor can push the cell cycle forward.
Tumor Suppressors
- Inhibit Cell cycle progression and cell division
- Mutations are usually recessive
- Loss of the tumor suppressor function is carcinogenic.
- Three classes
1. Gatekeepers
2. Landscapers
3. Caretakers
Gatekeepers
Act through Checkpoints
-PRB and P53
Caretaker
Act in genome maintenance
ATM and ATR
BRCA 1 and 2
Landscapers
Act in contact inhibition between cells (cell-cell interactions)
PTEN
Gatekeeper PRB
- Negative regulator of G1/S checkpoint
- Regulate S phase initiation
Gatekeeper P53
-Multifunctional tumor suppressor protein that induce apoptosis
-Block cell progression at various points.
activated by ATM or ATR (present at all DNA damage chpts throughout the cycle)
-Induce transcription of downstream genes.
Caretaker ATM and ATR
- Acts as a DNA damage sensor and regulates P53 activity
- Activated by Double stranded DNA damage
- Activate DNA repair, apoptosis, and BRCA signaling
-ATR is activated by single stranded DNA damage.
Caretakers BRCA 1
- Human genes that produce tumor suppressor proteins. to help repair DNA damage and ensure stability the cell’s genetic material.
- Stimulate homologous recombination for DS DNA damage
- Minimize gross chromosomal rearrangement because mutations are frequent in Ds breaks
- Leads to loss of heterozygosity (LOH)
- Mutations lead to decrease recombinational repair. defects will increase the risk of breast cancer.
Landscaper PTEN
- Lipid phosphatase that acts in opposition to PI3K
- Slow cell growth via dePO4lation of PIP3 to PIP2 which inhibits cell growth signals
- PTEN is activated by paracrine signals
Programmed cell death
-Apoptosis (more common), autophagy and necrosis.
Apoptosis
Specialized cell death that activates Apoptosome “wheel of death”
- Intrinsic pathway activated by mitochondrial permeabilization
- Extrinsic pathways activated by TNF alpha family
Apoptosome
- Needs to be activated by cytochrome C which comes from the mitochondria.
- CyctC binds to Apaf-1 to stimulate APaf 1- ATPase activity.
- ATP hydrolysis will trigger the assembly of apoptosome which activates the caspase cascade that leads to the apoptotic proteolysis.
Extrinsic Pathways
1-Death receptors: on cell surface activated by TNF cytokine superfamily
2-DISC: death inducing signaling complex activate procaspase protease zymogens.this activates caspase.
-Caspase: active protease that cleaves substrate proteins needed for genome integrity.
Intrinsic Pathway
-Initiated by MOMP ( mitochondrial outermembrane permeabilization) which release cytC
-CytC triggers assemply of apoptosome.
-
BCL2
Family proteins that regulates MOMP’s and apoptosis
- BCL2 and BCL-XL: anti apoptotic
- BAD and BAX: pro-apoptotic.
