Quiz 2 - Molecular Mechanisms of Disease

Oncogenes

Protooncogene

allows cells to enter and complete the cell cycle - promotes cellular proliferation

mutations converting protooncogene → oncogene

gene amplification, point mutation, translocation, truncation

First evidence of chemical agent causing cancer

1915: coal tar induced squamous cell carcinoma

Oncogenes are related to

transforming retroviruses

kinase

an enzyme that catalyzes the transfer of a phosphate group from ATP to specifies molecule - phosphorylation

gene amplification

increased copy number - ERBB2 (HER2)

point mutation

ras

translocation

BCR-ABL

truncation

EGFR

HER family proteins

regulate cell survival, growth and differentiation

HER2

ligand-independent protein, coded by ErbB2 gene

protein overexpression

mRNA overexpression

mRNA stabilization

protein stabilization

Ras

GTPase enzyme

promotes cell division

Ras mutation

decrease GTPase activity of Ras, increase the rate of exchange bound GDP for GTP

point mutation activating ras

glycine (protooncogene) for valine (oncogene)

GLY→ VAL

causes decreased GTPase activity

greater amounts of Ras/GTP complex (signaling pathway stays on)

Ras is downstream from

HER family

translocation example

BCR-ABL

BCR-ABL

causes chronic myeloid leukemia

deletion/truncation

EGFR

truncation of EGFR

results in constitutive activation of the receptor

myc

transcription factor that givers decisions to proliferate or differentiate

myc gene amplification

n-myc amplification is seen in 40% neuroblastomas

myc insertional mutation

uncontrolled proliferation (chicken virus)

myc translocation

lgH and c-myc → mys overexpression

receptor tyrosine kinases (RTK)

EGFR and HER2

non receptor tyrosine kinases

Src and ABL

serine/threonine kinases

AKT and Erk1 & 2

PDGF

promotes migration and proliferation

EGF

promotes proliferation

HGF

promotes cell motility

ligand independent activation of RTKs (become oncogenic)

amplification, truncation, point mutation, translocation

amplification of RTK

HER2

Truncation of RTK

EGFR

point mutation of RTK

EGFT

oncogenic form of EGF lacks

extracellular domain

autocrine growth factor

auto signals/self stimulates

RTK dimeric receptors become activated by

autophosphorylation

JAK/STAT signaling

JAK phosphorylates STAT → phosphorylated IFN receptor

serine/threonine kinases

become activated by autophosphorylation

PI3K can be activated by

ras, g-coupled receptor, RTK activation

Ras can activate

PI3K and MAPK pathways

PI3K→

PIP3→AKT

Ras→RAF→

MEK→ERK

PI3K functions

attaches phosphate to phospholipid; PIP2→PIP3; activates AKT

PTEN

converts PIP3 to PIP2 to prevent AKT binding

action of PI3K is opposed by

PTEN

BRAF(v600E)

found in 50% melanoma

inhibition of HER2 leads to

dephosphorylation of ERK