Signal transduction: When a cell receives an extracellular cue which ittransduces into the
cell to affect intracellular signaling pathways.
End results: Affected gene expression.
Tumor Virus: A cell-free filtrate held to be a virus that is responsible for a specific
neoplasm in humans or animals.
A virus may be tumor forming depending on species (Cold virus
causes tumor in mice).
Mitogenesis: Induction of mitosis.
c-Src: Src Kinase promotes mitogenesis.
Off state: On State:
- CSK phosphorylates - Protein Tyrosine Phosphatase
Y527. dephosphorylates Y527
- Y527 binds Src SH2 - Release Kinase domain
domain (Active site exposed)
(intramolecular) - Tyrosine Kinases
- Active site closed phosphorylate Y416 in active
(Inaccessible to site
tyrosine residues) (Increases Src kinase activity)
v-Src: An analog of c-Src found in tumors.
Y527 domain is absent.
Kinase domain is constitutively active in the absence of external
v-Src is an oncogene.
MMTV Mouse Mammary tumor virus
MMTV promoter Highly associated with the mammary gland, but doesnot depend on
Facilitates experiments on the mammary-epithelial specific
expression of genes in transgenic mouse models.
Murine Polyomavirus Transforms numerous epithelial cells in mice.
Middle T antigen Prominent oncogene.
Induces fast transformation by recruiting c-Src andkeeping it active.
Src phosphorylates 2 tyrosine, Activating pl3 kinase & Ras. ~~>
Phenocopying Epigenetics mimics genotype.
P53 Induced by DNA damage or viral infection that blocks cell cycle
progression (G1 or G2) until DNA is repaired or itinduces apoptosis
of virally infected cells.
P53 is NOT an oncogene! P53 inactivating Their action results in loss of p53 cell cycle checkpoint.
proteins Virally infected cells evade cell cycle arrest andapoptosis.
- Increased genomic instability, accumulation of mutations in
1. Sequestering p53
o Large T antigen (SV40)
o E6 (HPV)
o E1B (EBV)
2. Inducing degradation via MDM2 by sequestering USPs(De-
o EBNA1 (EBV)
3. Blocking p53 DNA-binding activity
o NS5A (HCV)
pRB A tumor suppressor that mediates G1 checkpoint controls
Activation of Cyclin CDK leads to phospholytation of Rb
- Underphosphorilated - Phosphorylated Rb releases E2F.
Rb binds & - E2F is active.
inactivates E2F TFs. - E2F an induce transcription of
- Cell remains in G1. genes required for progression
into S phase
(fos, myc, cyclin E, cyclin A)
Tumor Viruses & Rb Tumor viruses will block Rb, leading to loss of G1checkpoint.
Oncovirus expresses proteins that bind to Rb, releasing E2F
Oncovirus express proteins reducing p16 expression.P16 turns off
CDK. CDK cannot phosphorylate E2F. Activate E2F
Cell procedes into S-phase. Cyclin/CDK complexes
Viruses affect Cyclin CDK complexes to highjack
cell cycle checkpoints.
EBV EBV (BHRF1) protein is a viral BCl2 homologue. Cannot be inactivated
by BH3 containing protens.
Increases cellular BCL2 expression.
Binds Cyclin A/CDK 2 and stimulates its Kinase activity.
HTLV Increases Cellular Cyclin D1 expression
KSHV KSHV protein (v-FLIP) encodes a viral protein thatinhibits FAS-
Expresses v-Cyclin, Cyclin D1 homologue.
Cytotoxic genes Genes toxic to a cell Definitions:
Phosphatidylinositol A negatively charged phospholipid that is found inall eukaryotic
Phosphatic acid backbone, linked to an inositol molecule via
phosphate head group.
Unlikely to have a structural role in membrane because present at
low level. Steady state maintained.
Myoinositol A six carbon carbohydrate molecule with OH groups on each carbon.
Inositol Kinases Add Phosphate groups to carbons. Activity regulatedby intracellular
Inositol Phosphatase Removes phosphates on carbon. Activity regulated byintracellular
Phosphatidylinositol Signaling pathway activated by Phosphatidylinositol(PI) which
Signaling regulates numerous biological processes including:
- Cell motility
Mediated by switches from PI to PI 4-Phosphate to PI 4-
PLC/Phospholipase C Cleaves PIP to generate IP and DAG
IP3 Second messenger, potentiates calcium signaling.
- Opens IP R3channel, calcium leaves ER.
- STIM1 then goes to ER/plasma membrane contact sitesand
opens ICRAC(Ca channel). Extracellular Ca enters cytoplasm.
Increased calcium levels in cell regulates large amount
DAG Second messenger
GPCR G protein coupled receptors
Seven-trans membrane domain receptors located on plasma
Undergo a conformational change upon ligand binding, alpha
subunit dissociates, can activate genes.
Activates many PLC family members
PLCγ Only member with SH2 domain
Binds to phospho-tyrosine on RTK PLC
RTK Phosphorylates tyrosine, activating PLCγ and bringing it signaling