Lecture 13: Cell Cycle, Cancer, and Cell Death Flashcards
5 stages of M Phase
- Prophase - mitotic spindle assembly
- Prometaphase - nuclear envelope gone, spindle attach to chromosome
- Metaphase - chromosomes attach to mitotic spindle
- Anaphase - cohesion proteins cleaved, chromosomes pulled apart
- Telophase - nuclear membrane reconstitutes around chromosome sets
G0 phase, G1 phase, S phase, G2 phase
G0 - quiescent, non-cycling, intact proliferation capacity
G1 - between cell division and DNA replication initiation (build cell mass)
S phase - DNA replication (synthesis)
G2 phase - between DNA replication and initiation of cell division
When are Cyclins B, D1, E, and A active during the Cell Cycle?
D1 - G1 phase
E - end of G1 to S phase
A - S phase
B - G2 phase to M phase
What is the purpose of CAK (CDK activating kinase)?
phosphorylates threonine residue on T-loop of Cyclin Dependent Kinase
- allows catalytic function of CDK to become activated
Cdc25 A and B phosphatase: what are their substrates and what do they promote?
Cdc25A:
- Cdk1 –> G1 to S transition
- Cdk2 –> G2 to M transition
Cdc25B:
- Cdk1 –> G2 to M transition
Cdk4/6: What are their cyclin partners and what is their function?
partners: D cyclin
function: passage of restriction point and E cyclin synthesis
Cdk2: What is its cyclin partners and what is its function?
partners: E and A cyclin
function: G1 to S transition
Cdk1: What is its cyclin partners and what is its function?
partners: A and B cyclin
function: G2 to M transition
- A destroyed in prometaphase
- B destroyed when chromosome attach to spindle
What are the CKIs for Cyclin D?
p16 (INK4A), p15 (INK4B), p18 (INK4C), p19 (INK4D)
What are the CKIs for Cyclin E, A, and B?
p57, p27, p21
What is the function of p21?
- induced by p53 tumor suppressor
- cell cycle arrest after DNA damage (NO DNA synth)
- promotes cell cycle arrest in sensecence and terminal differentiation
What is the function of p27?
- cell cycle arrest in response to growth suppressors (TGF-beta) and in contact inhibition/differentiation
What is the function of p16?
- works w/retinoblastoma susceptibility protein in growth regulation and cycle arrest in senescence
- altered in a high percentage of human cancers
What happens during G1/S transition?
- D/Cdk4 hyperphosphorylates pRb, allowing E2F to increase transcription of cyclin E and E2F1 genes
- E2F increases formation of cyclin E and E2F
G1 checkpoint during DNA damage
Fast pathway: Chk2 inhibits Cdc25, preventing Cyclin E - Cdk from being activated
Slow pathway: p53 stabilization, p21 upregulation, inhibition of Cyclin-Cdk complexes
G2 checkpoint during DNA damage
- Chk1/2 –> causes export of Cdc25 = inactive B1/Cdk1 accumulation
- p53 stabilization, p21 inhibits B1/Cdk1
Initiation of Carcinogenesis
- irreversible, no threshold
- caused by genotoxic agents (chemicals, radiation, viruses, ROS)
- activation of oncogenes/inactivation of tumor suppressors
- sequence change in cellular DNA
Promotion of Carcinogenesis
- occurs over long period of time, reversible in early stages
- cellular selection and CLONAL EXPANSION
- inhibition of cell death in initiated cells
Progression of Carcinogenesis
- irreversible changes in gene expression
- selection for optimal growth in response to cellular environment
- benign tumors into malignant neoplasms capable of invading and metastasizing distant sites
Oncogenes vs Tumor Suppressors
Oncogenes: genes that stimulate division/growth
- loss of control = unregulated cell growth/division
- “gain of function” mutation
- germline inheritance rarely involved
Tumor Supressors: check/inhibit cell division
- loss of control = cell growth/division
- “loss of function” mutation
- germline inheritance frequently involved
Three types of oncogenes
- Cellular proto-oncogenes –> retrovirus captured
- Virus-specific oncogenes –> behave like mutated cellular proto-oncogenes
- Cellular proto oncogenes –> mutated
Papillomavirus: tumor type and cofactors
Tumor Type: anogenital cancers, some upper airway cancers and skin cancer
Cofactors: smoking, oral contraceptives and genetic disorder, UV light, immunosuppression
Mechanism and Oncogenic element of: Type 1 retroviruses
- Transducing Viruses
- mech: oncogenic transduction of cellular gene
- element: cellular oncogene carried in retrovirus
Mechanism and Oncogenic element of: Type 2 retrovirus
- Non-transducing Viruses
- mech: cis-acting provirus
- element: cellular oncogene via proviral insertion/integration
Mechanism and Oncogenic element of: Type 3 retrovirus
- Non-transducing Long Latency Viruses
- mech: trans-acting proteins encoded by retrovirus
- element: retroviral transactivating protein disrupting normal regulation of cellular transcription
Mechanism and Oncogenic element of: Type 4 retrovirus
- Retroviruses that contain envelope that signals
- mech: trans-acting protein (envelope) encoded by retrovirus
- element: inappropriate cellular signaling resulting from viral envelope/cell receptor interactions
Oncogenes and their associated cancers:
- K-ras
- N-ras
- H-ras
- c-myc
- L-myc
- N-myc-DDX1
- K-ras –> lung, ovarian, colorectal, bladder carcinomas
- N-ras –> head and neck cancers
- H-ras –> colorectal carcinomas
- c-myc –> various leukemias, carcinomas
- L-myc –> lung carcinomas
- N-myc-DDX1 –> neuroblastomas, lung carcinomas
What happens if p53 is damaged and cannot be repaired?
programmed cell death occurs
What is the 2nd most commonly inactivated gene?
INK4A (p16)
Chemotherapy:
- Alkylating Agents
- Intercalating Agents
- Antimetabolites
- Mitostatic Agents
- Platinum Derivatives
- Alkylating - denature certain macromolecules (cross-link DNA chains)
- Intercalating - interact between 2 DNA bases, changing structure and function
- Antimetabolites - structural analogs of purine/pyrimidine (block synth of corresponding base)
- Mitostatic - inhibit tubulin synthesis (cell spindle poisons)
- Platinum Derivatives - DNA binding
Two molecules involved with regulating Necrosis and the mechanism
- Receptor-interacting protein 1 (RIP1)
- Poly [ADP-ribose] polymerase 1 (PARP-1)
Mechanism:
- Calcium overload, mito uncoupling, inc. oxygen consumption
- ATP depletion and excessive ROS
Morphology of Necrosis
Cell membrane: swell/rupture
Cytoplasm: organelle degen., mito swelling
Nucleus: clumping, random degen. of nuclear DNA
Cells: ALL TYPES
Inflammation: YES
- extensive failure of normal physiological pathways essential for maintaining cellular homeostasis
- CASPASE INDEPENDENT
Morphology of Apoptosis
Cell membrane: blebbing, fragment into membrane bound apoptotic bodies
Cytoplasm: fragment, shrinking
Nucleus: chromatin condensation/degradation by specific DNA cleavage = nuclear fragmentation
Cells: hematopoietic cells and malignant counterparts
Inflammation: NO
- cell membrane loses asymmetry, phosphatidylserine exposed on cell surface; CASPASE DEPENDENT
4 apoptotic mechanisms
- DNA damage (ATP and p53)
- Death receptor signaling
- cell membranes (hydrolysis of sphingomyelin to ceramide)
- mitochondrial damage - ceramide mediated process
Bcl-2, Bax, Bak, BH3 (Apoptotic Signals)
- Bcl-2 inhibits Bax and Bak
- BH3 binds to Bcl-2, allowing Bax and Bak to oligomerize (pore formation)
Morphology of Autophagy
Cell membrane: blebbing
Cytoplasm: accumulation of two-membrane autophagic vacuoles
Nucleus: partial chromatin condensation; no fragments
Cells: ALL TYPES
Inflammation: NO
- CASPASE INDEPENDENT, increased lysosomal activity
Morphology and mechanisms (3) of Mitotic Catastrophe
Cell membrane: no change
Cytoplasm: larger cytoplasm; formation of giant cell
Nucleus: micro/multinucleation. formation of nuclear envelopes around individual clusters of missegregated chromosomes
Mechanisms:
- defects in cell cycle checkpoints
- hyperamplification of centrosomes
- caspase-2 activation during metaphase (delayed apoptosis)
Fate of Cells w/Abberant Mitosis (Mitotic Catastrophe)
- Mitotic Death (die in mitosis)
- Delayed Cell Death (division for many cycles)
- Senescence (exit mitosis, permanent G1 arrest)
Morphology and two pathways of Senescence
Cell membrane: No change
Cytoplasm: flattening, inc. granularity
Nucleus: distinct heterochromatic structure
Cells: ALL TYPES
Inflammation: Yes, but induced by secretory factors from cell itself
Pathways (same as DNA damage checkpoints)
- p53 –> p21
- p16 –> Rb
Rous Sarcolema: oncogene, type of oncoprotein, homologous oncogene in human tumors
oncogene: src
oncoprotein: non-receptor TK
homologous oncogene: colon carcinoma
