Neoplasia #6: Apoptosis and DNA Repair

Bcl-2

Inhibits apoptosis

Example: follicular lymphoma

• Gain of function → bcl-2 on overdrive → excessive proliferation without control

p53

triggers apoptosis

• Loss of function will prevent apoptosis → proliferation

Regulation of apoptosis

• Can be gain or loss of function depending on what the protein did originally

One method of p53 activation of apoptosis

• Bcl-2 and bcl-xL - “evil twins” → non-apoptosis

• Bax and Bak - “good twins” → apoptosis

Intrinsic mitochondrial pathway of apoptosis

Radiation injury → p53 → Bax-induction

** Know about caspases

Act activity results in

anti-apoptosis Bcl-2 and Bcl-xL proteins binding to Bax and Bak → prevents intrinsic apoptotic pathway

Active PTEN in suppression of cell survival

No Act or Bcl-2 activation → accumulation of Bax → pore formation → apoptosis

Suppression of cell survival by PTEN

PTEN deleted → leads to excessive survival and growth → cancer

• Defective PTEN activity in 60% malignant prostate cancers

PTEN is the 2nd most frequently mutated gene in human cancer after p53

Bid links the extrinsic to intrinsic apoptotic pathways

Need to know these pathways for BOARDS

HNPCC (Lynch syndrome) is the most common cause of hereditary colon cancer. This is a result of

defect in DNA mismatch repair genes - MLH1, MSH2, MSH6, PMS2 — creates “micro satellite instability “ repeat sequences

** TGFBR2 (TGF-beta receptor II) mutated in 70% HNPCC colon cancer

HNPCC - hereditary nonpolyposis colorectal cancer (AD, incomplete penetrance)

What happens in xeroderma pigmentosum (XP)?

• Failure of nucleotide excision repair (impairment of DNA excision repair mechanisms)

• Cannot repair UV light damage to DNA )(include pyrimidine dimer formation)

Colon cancer without polyps (HNPCC; Lynch syndrome) risk of other cancers

• Males: 90% risk colon cancer

• Females: 70% risk colon cancer, 40-60% risk endometrial cancer

Rare AR disorders - chromosomal instability syndromes (3 examples)

• Xeroderma pigmentosum

• Ataxia telangiectasia

• Fanconi anemia

Ataxia telangiectasia - mutation and defect

• Mutation of ATM

• Defects in DNA damage signaling → defective dsDNA repair by homologous recombination

• Failure of cell cycle checkpoint system

Ataxia telangiectasia - important features

• Extreme radiosensitivity

• Immunodeficiency

• Predisposition to cancer - lymphoma

• Sterility

• Ocular and facial telangiectasia

• Cerebellar ataxia

Common cancer mutations summary

Common cancer mutations summary page

__ activated in 90% cancer cells → immortalization

Telomerase