1. Prophase - mitotic spindle assembly 2. Prometaphase - nuclear envelope gone, spindle attach to chromosome 3. Metaphase - chromosomes attach to mitotic spindle 4. Anaphase - cohesion proteins cleaved, chromosomes pulled apart 5. Telophase - nuclear membrane reconstitutes around chromosome sets

Lecture 13: Cell Cycle, Cancer, and Cell Death Flashcards by Tom Porter

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

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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

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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

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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

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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

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Cdk4/6: What are their cyclin partners and what is their function?

partners: D cyclin
function: passage of restriction point and E cyclin synthesis

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Cdk2: What is its cyclin partners and what is its function?

partners: E and A cyclin
function: G1 to S transition

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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

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What are the CKIs for Cyclin D?

p16 (INK4A), p15 (INK4B), p18 (INK4C), p19 (INK4D)

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What are the CKIs for Cyclin E, A, and B?

p57, p27, p21

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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

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What is the function of p27?

cell cycle arrest in response to growth suppressors (TGF-beta) and in contact inhibition/differentiation

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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

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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

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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

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G2 checkpoint during DNA damage

Chk1/2 –> causes export of Cdc25 = inactive B1/Cdk1 accumulation
p53 stabilization, p21 inhibits B1/Cdk1

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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: 1. K-ras 2. N-ras 3. H-ras 4. c-myc 5. L-myc 6. N-myc-DDX1

1. K-ras --> lung, ovarian, colorectal, bladder carcinomas 2. N-ras --> head and neck cancers 3. H-ras --> colorectal carcinomas 4. c-myc --> various leukemias, carcinomas 5. L-myc --> lung carcinomas 6. 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: 1. Alkylating Agents 2. Intercalating Agents 3. Antimetabolites 4. Mitostatic Agents 5. Platinum Derivatives

1. Alkylating - denature certain macromolecules (cross-link DNA chains) 2. Intercalating - interact between 2 DNA bases, changing structure and function 3. Antimetabolites - structural analogs of purine/pyrimidine (block synth of corresponding base) 4. Mitostatic - inhibit tubulin synthesis (cell spindle poisons) 5. Platinum Derivatives - DNA binding

Two molecules involved with regulating Necrosis and the mechanism

1. Receptor-interacting protein 1 (RIP1) 2. 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

1. DNA damage (ATP and p53) 2. Death receptor signaling 3. cell membranes (hydrolysis of sphingomyelin to ceramide) 4. 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: 1. defects in cell cycle checkpoints 2. hyperamplification of centrosomes 3. caspase-2 activation during metaphase (delayed apoptosis)

Fate of Cells w/Abberant Mitosis (Mitotic Catastrophe)

1. Mitotic Death (die in mitosis) 2. Delayed Cell Death (division for many cycles) 3. 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) 1. p53 --> p21 2. p16 --> Rb

Rous Sarcolema: oncogene, type of oncoprotein, homologous oncogene in human tumors

oncogene: src oncoprotein: non-receptor TK homologous oncogene: colon carcinoma