Bimm 110 Section 7 Slides

BIMM 110 Section 7 May 27, 2009 George Chen [email protected] www.pdfcoke.com/g_chen

12

DAYS UNTIL

FINAL

Announcements ●

Extra section Friday of 10th week?

Outline ●

Intracellular signaling ●

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GTP binding

Cyclins

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HPV

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Breast cancer

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Colon cancer

Ras HER signaling ●

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Phosphorylation

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Herceptin

Philadelphia chromosome ●

Gleevec

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Burkitt's Lymphoma

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End replication problem

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HNPCC

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FAP

Bcl2

Recall: Intracellular signaling Phosphorylation ●

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ATP adds a phosphate group to an inactive protein using a protein kinase. A phosphate is removed from an active protein using a protein phosphatase

GTP binding ●

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GTP binds to an inactive protein GTP is released through hydrolysis to turn off a protein

Ras ●

A G-protein

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Uses GAP/GEF

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Activated by RTK

Function ●

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Activates MAP kinase cascade to promote cell proliferation and survival 20-30% all cancers have Ras mutations ●

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Inappropriately activated Perpetually active

Mitogen Activated Protein Kinases (MAPKs)

A MAPK, ERK ●

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Leads to downstream phosphorylatio n Changes gene expression and protein activity Cell proliferation and growth

Possible Ras Mutations ●

Increase GEF

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Mutant GEF

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Decrease GAP

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GAP mutations

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Increase expression mutations

Human Epidermal Growth Factor Receptor (HER) Mutations ●

Too much ligand

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Too much receptor

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Too little receptor degradation/regulati on Increased signal transduction Factor independent

Treatment ●

Herceptin – monoclonal antibody inhibiting HER2 activity

HER

MAP

Philadelphia Chromosome ●

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Chronic Myelogenous Treatment Leukemia ● Gleevec Superactive Abl TK

Burkitt's Lymphoma ● ●

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Myc overproliferation Activates cell proliferation Activates telomerase expression

Treatment ●

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Rituximab, a monoclonal antibody against CD20 Chemotherapy

Recall End Replication Problem ●

Telomeres

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Telomerase

Cyclins & Cyclin-dependent kinases ●

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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 ●

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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

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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 ●

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BRCA1/BRCA2 mutations

Sporatic breast cancer ●

Mostly estrogen receptor related (ER)

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Treated by blocking ER

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Rest may be treated with Herceptin

Colorectal cancer Hereditary Nonpolyposis Colon Cancer (HNPCC)

Familial Adenomatous Polyposis (FAP)

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Autosomal dominant

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100's of polyps

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One or few polyps

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Autosomal dominant

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Mutation in DNA mismatch repair genes Multistep

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Mutation in APC genes Multistep carcinogenesis

Wnt and β-Catenin ●

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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

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Necrosis: Unregulated

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Mitochondria play a major role in regulation

Bcl-2 ●

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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