Cell cycle, cancer, and cell death

Question 1

G0 phase

Answer 1

quiescent, intact proliferation capacity, non-cycling

Question 2

G1 phase (gap 1)

Answer 2

duration between completion of cell division and initiation of DNA replication, where cells start building cell mass

• growth and preparation
• RNA and protein synthesis also take place here. Organelles are duplicated

Question 3

S-phase (synthesis)

Answer 3

DNA replication
multiple replication forks are activated on each chromosome
- then chromosomes are condensed into heterochromatin
- time during this phase is fairly constant across cell types

Question 4

G2-phase (gap 2)

Answer 4

duration between completion of DNA replication and initiation of cell division

• preparation for nuclear division in mitosis
• there is a checkpoint that assess nuclear integrity, ensures that DNA is intact

Question 5

M-phase

Answer 5

mitosis

- prophase, metaphase, anaphase, telophase

Question 6

Cdc25

Answer 6

dephosphorylates the cyclin-CDK complex at its inhibitory site, activating the cyclin

Question 7

CDK1

Answer 7

partners with cyclins A and B
triggers G2 –> M transition. Cyclin A is synthesized in S and destroyed starting at prometaphase
Cyclins B are synthesized in S/G2 and destroyed following the completion of chromosome attachment to the spindle
CKI (inhibitors p57, p27, p21) kip family

Question 8

CDK2

Answer 8

cyclins A, E
Triggers G1 –> S transition
- stabilizes the replication complexes during DNA replication at the replication forks
CKI (inhibitors p57, p27, p21) Kip family

Question 9

CDK4, CDK6

Answer 9

cyclin partner D
phosphorylation of the retinoblastoma susceptibility protein in G1. Triggers passage of the restriction point and cyclin E synthesis in some cell types. Extracellular growth factors control synthesis of D cyclins
CKI (inhibitor) - P16, p15, p18, p19 (INK family)

Question 10

p16 CKI

Answer 10

Inhibits Cdk4 and Cdk6
Cooperates with retinoblastoma susceptibility protein in growth regulation. Altered in a high percentage of human cancers. This gene overlaps teh gene for p19, an important regulator of the p53 tumor suppressor protein.

Question 11

p21 CKI

Answer 11

inhibits most CDK-cyclin complexes
- induced by p53 tumor suppressor. Cell-cycle arrest after DNA damage. Binds PCNA and inhibits DNA synthesis. Promotes cell cycle arrest in senescence and terminal differentiation. At low levels, may help assemble active Cdk-cyclin complexes

Question 12

p27 CKI

Answer 12

inhibits most CDK-cyclin complexes

- cell cycle arrest in response to growth suppressors like TGF-B and in contact inhibition and differentiation.

Question 13

cell cycle entry and progression

Answer 13

extracellular signals regulate cell cycle proteins and control growth
- Ras superfamily receive signals from catalytic receptors that have been activated by their ligand, overall effects of Ras signaling involve induction of proliferation

Question 14

R point

Answer 14

restriction point, where cells commit to going through the cell cycle, regulated by retinoblastoma protein Rb
- unphosphorylated Rb inhibits E2F. Cyclin phosphorylate Rb, then CDK2/E hy[erphosphorylate Rb and it liberates E2F transcription factor

Question 15

G2/M transtition

Answer 15

• activation of CDK1/cyclin B at the G2/M boundary, maintained by Cdc25
• CDk1/cyclin B translocate to the nucleus to initiate spindle assembly
• activated anaphase-promoting complex (APC) destroy CDk1 freeing cyclin B for degradation

Question 16

G1 checkpoint

Answer 16

slow pathway:
- P21 binds and inhibits the CDk4/6/D.
- P21 is activated by P53 txn factor
- p21 and p53 are tumor suppressors
Faster pathway:
- activation of checkpoint kinase 2 and the inactivation of cdc25
- phosphates inactivating the cyclinD/CDK4/6 can no longer be removed and results in G1 arrest

Question 17

G2 checkpoints

Answer 17

ATM pathway - ATM senses DNA damage and signals downstream

Question 18

tumors

Answer 18

space occupying lesions that may or may not be neoplasms

Question 19

neoplasm

Answer 19

relatively autonomous abnormal growth with abnormal gene regulation
2 types: benign and malignant (–> cancer)

Question 20

cancer

Answer 20

malignant neoplasm (can produce metastasis)

Question 21

Metastasis

Answer 21

secondary growth of cancer at different location from the primary neoplasm

Question 22

Initiation

Answer 22

first step of carcinogenesis
- simple mutatino in one or more genes that control key regulatory pathways of the cell
Ex. genotoxic event (change in DNA sequence)
- irreversible, no threshold
- genotoxic agents such as chemicals, radiation, ROS, and viruses
- can be result of oncogenes or inactivation of tumor suppressor genes

Question 23

promotion

Answer 23

second step of carcinogenesis

• selective functional enhancement of signal transduction pathways that were induced by initiator by continuous exposure
  ex) . epigenetic event (involving changes in gene regulation)
• occurs over a long period of time, can be reversible in its early stages
• gene activation or repression –> clonal expansion
• threshold for time and dosing
  ex. ) inhibition of cell death

Question 24

progression

Answer 24

third step of carcinogenesis

• continuing change of the basically unstable karyotype
  ex) . clastogenic events and other (further changes in karyotypes)
• further complex genetic changes (translocations, deletions, gene amplifications), irreversible changes in gene expression
• karyotype instability
• selection for optimal growth in response to cellular environment
• conversion of benign tumors into malignant neoplasms

Question 25

Hallmarks of cancer

Answer 25

• acquire self-sufficiency of growth signals
• become insensitive to growth inhibitory signals
• evade cell death
• acquire limitless replicative potential
• sustain angiogenesis
• acquire capabilities to invade tissues and metastasize
• create genome instability
• promote inflammation
• avoid immune destruction
• reprogram energy metabolism

Question 26

Oncogenes

Answer 26

expression of these genes stimulate cell division and/or growth. Tightly controlled under normal circumstances. Loss of regulation of gene expression can lead to enhanced expression –> unregulated cell division and growth
- said to be “dominant”, result from gain of function mutation

Question 27

Tumor suppressor genes

Answer 27

genes that serve to check or inhibit cell division. Loss of expression of these proteins leads to cell growth or cell division

• in carciogenesis: inactivating mutations, deletions, loss of expression
• germline inheritance frequently involved in cancer development

Question 28

Viral oncogenes

Answer 28

Adenovirus, hepatitis B virus, Epstein-Barr virus, hepatitis C virus

Question 29

Human oncogene examples

Answer 29

Myc, Ras, cell cyclins, ATM, PDGF, EGF/EGFR, and DNA repair proteins

Question 30

Human tumor suppressor genes

Answer 30

p53, Rb, p14ARF, p16

- p16 inhibits cyclin CDK4/6, which in turn blocks their ability to phosphorylate Rb, halts cell cycle here

Question 31

Breast Cancer

Answer 31

heterogeneous disease with features including

• activation of human epidermal growth factor receptor 2 (HER2, encoded by ERBB2)
• activation of hormone receptors (estrogen receptor and progesterone receptor)
• BRCA mutations

Question 32

Estrogen receptor signaling pathway

Answer 32

breast cancer cells have relatively high ERa expression and low ERB expression.

• the hormone receptors form dimers upon ligand binding and translocation into the cell nucleus for txn regluation
• ER dimers bind to ERE region of target genes and recruit co-regulators
• also act as co-regulators for other transcription

Question 33

HER2 signaling pathway

Answer 33

• receptor tyrosine kinase located on the cell membrane and respond to a variety of ligands
• phosphorylation of tyrosine kinase domain in the cytoplasm initiates downstream oncogenic signal pathways such as PI3K/AKT and Ras/MAPK pathways

Question 34

Mechanisms of cell death

Answer 34

1. apoptosis: programmed cell death (suicide)
2. autophagy (self destruction, digestion)
3. necrosis (explosive disaster)
   Depending on morphological criteria
   - mitotic catastrophe
   - senescence (irreversible growth arrest - reproductive cell death)

Question 35

Necrosis

Answer 35

• uncontrolled form of cell death
• all cyell types involved, inflammation is present
• extensive failure of normal physiological pathways essential for maintaining cellular homeostasis: regulation of ion transport, energy production (ATP depletion) and pH balance
• cell membrane swelling and rupture, increased vacuolation, organelle degeneration, and mitochondrial swelling
• two key players involved (Rip1 and Parp1)

Question 36

Necrosis mechanisms

Answer 36

Ca2+ overload
- mitochondrial uncoupling
- increased O2 consumption
- excessive ROS production
- ATP depletion
no caspases involved

Question 37

Apoptosis

Answer 37

triggered by DNA damage (ATM, P52)

• death receptor signaling (CD95, Fas receptor, TNF receptor superfamily, and caspase8 mediated)
• cell membranes (activation sphingomyelinase and leading to hydrolysis of sphingomyelin to ceramide)
• mitochondrial damage (ceramide-mediated process, mitochondrial ceramide synthase activation)