Cell Cycle, Apoptosis, and Cancer Flashcards
Myc/Retinoblastoma Pathway
Myc upregulates G1-CDK; CDK phosphorylates Rb; Rb-P releases E2F; E2F (TF) drives cell from G1 to S
What cyclins and kinases are needed for Rb pathway?
CDK-4 and CDK-6 with Cyclin D
What genes do E2F promote transcription of?
Cyclin E for transition to S and Cyclin A for Synthesis stage; also upregulates CDK-2 which hyperphosphorylates Rb more
Phosphorylates T loop, bringing the cyclin-CDK complex to full activity
CDK-activating Kinase (CAK)
Cyclins and CDKs during each part of interphase
G1 - Cyclin D; CDK-4 and CDK-6
G1/S - Cyclin E; CDK-2
S - Cyclin A; CDK-2
G2 - Cyclin A and Cyclin B; CDK-1
Inhibits CDK via phosphorylation of roof site
WEE1
Reactivates CDK via dephosphorylation of roof site
Cdc25
Binds both CDK and cyclin to lower activity
P27(kip1); early cell cycle events
APC pathway
activated by binding of CDC20; APC poly-ubiquinates cyclins S and M; cyclins targeted for destruction in proteasome; less cyclins downregulates CDKs
E3 ubiquitin ligase that regulates p53
MDM2
p53 pathway
if DNA damage p53 is phosphorylated; no longer degraded and can upregulate CKI p21; leads to cell cycle arrest
binds and inactive cyclin-CDK complexes keeping Rb hypophosphorylated (inactive); transcription influenced by p53; mainly CDK-2!
p21
Forms a pore in the mitochondrial membrane in response to a pro-apoptotic stimulus
BAX
Intrinsic Pathway
BAX forms hole in mitochondria; cytochrome C leaves and binds with Apaf1 forming apoptosome; apoptosome activates caspase 9 which activates caspase 3,6, and 7
Extrinsic Pathway
TNF-alpha or Fas receptors activated; procaspase 8 cleaved; caspase 8 activates 3, 6, and 7
HER2 receptor as oncogene
Valine to Glutamine in RTK domain causes dimerization without a ligand (NEU); leads to breast cancer
EGF receptor as oncogene
deletion in RTK domain causes constitutionally active receptor (EGFRVIII); leads to glioblastoma
BCR-ABL translocation
translocation of ABL on 9 and BCR on 22 (Philadelphia chromosome); leads to BCR-ABL fusion protein; causes chronic myelogenous leukemia (CML)
Tumor Suppressor Functions
Repress cell cycle progression
Promote apoptosis
Couple DNA damage to the cell cycle
DNA repair proteins
Common tumor suppressors
RB1 encodes RB
TP53 encodes p53
PTEN - phosphate and tensin homolog
APC - adenomatous polypsis coli
Cell adhesion proteins that prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit tumor metastasis
Metastasis Suppressors
Antibody therapy directed towards HER2; blocks cleavage, dimerization, activates Ab mediated cytotoxicity, or internalizes HER2 for degradation
Trastuzumab (Herceptin)
Binds where ATP normally would on BCR-ABL enzyme, preventing CML
Mesylate (Gleevac)
Interphase steps
G1: RNA and protein synthesis for DNA replication
S: DNA synthesis
G2: DNA stability is ensured for mitosis
