BIMM 110 Section 7

May 27, 2009

George Chen
gtchen@ucsd.edu
www.scribd.com/g_chen
12
DAYS UNTIL
FINAL
 Announcements
●
Extra section Friday of 10th week?
 Outline
● Cyclins
● Intracellular signaling ● HPV
● Phosphorylation ● Breast cancer
● GTP binding ● Colon cancer
● Ras
● HNPCC
● HER signaling ● FAP
● Herceptin ● Bcl2
● Philadelphia chromosome
● Gleevec
● Burkitt's Lymphoma
● End replication problem
 Recall: Intracellular signaling
Phosphorylation GTP binding
● ATP adds a ● GTP binds to an
phosphate group to inactive protein
an inactive protein ● GTP is released
using a protein through hydrolysis to
kinase. turn off a protein
● A phosphate is
removed from an
active protein using a
protein phosphatase
 Ras
● A G-protein Function
● Uses GAP/GEF ● Activates MAP kinase
● Activated by RTK cascade to promote
cell proliferation and
survival
● 20-30% all cancers
have Ras mutations
● Inappropriately
activated
● Perpetually active
Mitogen Activated Protein Kinases
(MAPKs)
A MAPK, ERK

● Leads to
downstream
phosphorylatio
n
● Changes gene
expression and
protein activity
● Cell
proliferation
and growth
Possible Ras Mutations
● Increase GEF
● Mutant GEF
● Decrease GAP
● GAP mutations
● Increase expression
mutations
 Human Epidermal Growth Factor
Receptor (HER)
Mutations Treatment
● Too much ligand ● Herceptin –
● Too much receptor monoclonal antibody
inhibiting HER2
● Too little receptor activity
degradation/regulati
on
● Increased signal
transduction
● Factor independent
 HER

MAP
 Philadelphia Chromosome
● Chronic Myelogenous Treatment
Leukemia ● Gleevec

● Superactive Abl TK
 Burkitt's Lymphoma
● Myc overproliferation Treatment
● Activates cell ● Rituximab, a
proliferation monoclonal antibody
● Activates telomerase against CD20
expression ● Chemotherapy
 Recall End Replication Problem
● Telomeres
● Telomerase
Cyclins & Cyclin-dependent kinases

● Cyclin and CDK form a

complex to activate cell
cycle events
● Cdk Inhibitor Protein
(CKI) such as p27 and
p21 prevent complex
activation
● Transition from G1 to S
phase promoted by Myc
● Rb phosphorylated to
release E2F
 Cell cycle mutations
● Cell cycle has several checkpoints to repair
DNA damage
● Key regulators: ATM (ataxia telangiectasia,
mutated) and ATR (ATM and Rad3-related)
protein kinases
● ATM: Double strand breaks
● ATR: UV damage
● ATM/ATR phosphorylate many proteins,
including Chk1/Chk2, p53
 HPV
● Major cause of cervical cancer
● Virus produces proteins E6 and E7 that
promote cell proliferation by binding to Rb and
p53
 Breast cancer
● Affects 10% of women in U.S.
● 20% of cases have a significant genetic/familial
component
● BRCA1/BRCA2 mutations
● Sporatic breast cancer
● Mostly estrogen receptor related (ER)
● Treated by blocking ER
● Rest may be treated with Herceptin
 Colorectal cancer

Hereditary Familial
Nonpolyposis Colon Adenomatous
Cancer (HNPCC) Polyposis (FAP)
● Autosomal dominant ● 100's of polyps
● One or few polyps ● Autosomal dominant
● Mutation in DNA ● Mutation in APC
mismatch repair genes
genes ● Multistep
● Multistep carcinogenesis
 Wnt and β-Catenin
●
β-catenin is not degraded
when APC is mutated
●
β-catenin accumulates,
overactivates cell
proliferation genes
 Cell Death
● Apoptosis: Regulated
● http://www.youtube.com/watch?v=mHOX43-4PvE
● Necrosis: Unregulated
● Mitochondria play a major role in regulation
 Bcl-2
● Controls the release of cytochrome C into the
cytosol (BH123 aggregate protein)
● Bcl-2 anti-apoptotic proteins prevent the
aggregation of BH123 proteins
● Excess Bcl-2 confers decreased sensitivity to
apoptotic signals