Exam 3 - Cancer 2

Question 1

What are tumor supressor genes

Answer 1

• 2 types
• 1. ) Proteins that normally restrict cell growth and proliferation
     * inhibt progression through g1/S
     
     • ex: Rb and CKI
       * Receptors or componets of a signaling pathways that inhibt proliferation
       * promote apoptosis
     • Ex: Caspases
• 2. ) proteins that maintain the integrity of the genome
     * check point control
     
     • ATM, ATR both detect DNA damage and stop cell cycle
       * ATM***********TEST
       * DNA Repair Enzyme of pathways
• If these tumor supressors genes are lost then cancer can occur
  
  • requires 2 recessive mutations
    *

Question 2

How is retinoblastoma and tumor suppressors related?

Answer 2

• inherited eye cancer in children
• Rb is a tumor supressor that inhibits progression into S phase
• Need to lose both gene Rb
• 2 forms
  
  • 40% is familial where both eyes are affected
  • 60% is sporadic (no family history) single tumor in one eye
• can occur in both tumor supressors (Rb) and oncogene (CKI)
  
  • in the onco version
    
    • CKI IS ABSENT so Cdk Cyclin is always active and will phosphorlate Rb to deactivate it and that allows proliferation to continue
    • In regular version
      
      • CKI is present to inhibit CDK from phosphorlatying Rb so that Rb cant stop progression into g1/S phase

Question 3

What is the hereditary form of Retinalblastomia

Answer 3

• Family form (hereditary)
• loss of function or deletion of 1 copy of Rb in every cell
• predisposed to cancer
• 1 copy of Rb gene
• Eliminates one good copy and tumor forms
• loss heterozygosity (LOH)

Question 4

What is the sporadic form of Rb

Answer 4

• Non hereditary = start off with normal cells
• Two hit hypothesis
  
  • first Rb gene obtains mutation then second mutation Rb
  • Familial already has one mutation so they are predisposed to cancer
  • Sporadic
    
    • 2 normal Rb genes
      
      • requires 2 mutations or “hits”
        
        • MUCH More rare than hereditary form
          *

Question 5

How are tumor suppressors inactivated or lost in Rb?

Answer 5

Question 6

What is P53?

Answer 6

• Huge tumor suppressor gene
• P53 is involved in
  
  • Cell cycle arrest
  • Dna Repair
  • Apoptosis
  • Block of angiogenesis
• P53 is VERY important because majority of cancers have p53 mutation

Question 7

WHat happens if you lose P53?

Answer 7

• Loss checkpoint control in cell cycle
• loss of cell cycle arrest in response to DNA damage
• loss of DNA repair activites
• Loss of apoptosis in response to DNA damage
• p53 is a gene regulatory protein
  
  • Stimulates transcription of gene encoding CKI (cdk inHibitory protein) called P21
  • P21 binds to g1/S-Cdk and S-Cdk and so will stop the cycle
  • p53 also activates expression apoptotic proteins BH123 and Bh3

Question 8

What kind of factors(signals ) does p53 react to and what are the effects ?

Answer 8

• Reacts to:
  
  • Hyperproliferative signals
  • Dna Damage
  • Telomere shortening
  • hypoxia
• Causes :
  
  • Cell cycle arrest
  • senescence
  • apoptosis

Question 9

What is a DNA tumor Viruses and an example of one?

Answer 9

• Pailloma viruses is the exampleand can cause warts and cervical cancer
• Viral DNA exists as extrachromosomal material (like plasmid in bacteria)
• Normally the replication of the viral DNA coincides with replication of chromomse
• however once viral DNA intergrates with host DNA it can interfere with the control of cell devision in basal cells and can cause a maignant tumor to develops

Question 10

WHat are the viral proteins of the papilloma virus ?

Answer 10

• The viral proteins that cause malignancy are E6 and E7
• These bind to 2 tumor suppressor genes Rb + p53
• CEels can replicate in an uncontrolled manner

Question 11

How does normal pathway and the viral pathway for proliferation of DNA tumor viruses compare?

Answer 11

• Normal
  
  • Rb bound to E2F protein (gene regulatory protein) to inactivate transcription of cycllins and production of g1/s Cdk and S cdk does not happen
  • p53 induces expression of p21 (a CKI) to prevent activity of CDK
  • blocking proliferation
• VIral Protein
  
  • E7 binds to Rb causes E2F to overexpress g1/S-CDK and S Cdk and cell grows and Divides
  • E6 binds to p53 and inactivates it and so CKI (p21) is NOT produced
  • Cell proliferation is activated by the virus

Question 12

How doe Onco genes and tumors compare?

Answer 12

• Overativity mutations: gain of function - ONCOGENES - involve single mutation event and activation of gene causing proliferation (dominant)
• • Underactivity mutations: loss of function - TUMOR SUPPRESSORS GENES - involve genes that inhibt growth. Mutation event: one gene no effect; second mutation causes probelms (recessive)

Question 13

What is a proto-onco gene?

Answer 13

• Normal gene that is usually involved in refulation of cell proliferation that can be converted to cancer causing oncogene by mutation
• Transgenic mice are tools for tudying oncogene

Question 14

How does the Myc and Ras work as oncogenes sepeperatly and collectively?

Answer 14

• in MYC Tg, cell proliferation occurs but most cells do not give rise to cancer
• Ras Tg mouse tumors occurs as a more severe rate
• MYC Tg x Ras Tg mouse devlope tumors at a higher rate

Question 15

What is Bcl-2 ?

Answer 15

• First identified as an oncogene
• Blc2 expression is elevated by a chromosomal translocation in b-cell lymphoma
• blc2 mutation stops apoptosis

Question 16

WHat are the barriers for cancer cell metastais ?

Answer 16

Question 17

Why is colorectal cancers the most preventable cancers?

Answer 17

Colonscopy reveal early detection and it takes 10 years for tumor pregression so there is a lot of time to check

Question 18

What is a polyp?

Answer 18

• Is a precursor of cancer (including colorectal cancer)
• Cur off polyp = cure
• if left alone malignan tumor develops from adenoma (polyp)

Question 19

What is colorectal cancer?

Answer 19

• Ariseing in the epithelial lining of large intestine.
• Gut is renewed at a rapid rate via stem cells and is a highly organized epithelium in large intestine
• Mutations that disrupt organizaton signals begin tumor progression for colorectal cancer
• colon cancer can detect small protroding benign tumor called polyp =adenoma

Question 20

What are some mutations that are common in colorectal cancer?

Answer 20

• 40% of colorectal cancers have point mutationin K ras
• 60% inactiving mutation of p53
• important loss is APC mutation

Question 21

What is hereditary colorrectal cancer?

Answer 21

• Familial adenomatous polyposis coli (FAP)
• Hundred of polyps
  
  • at lease one will will become maligant
• caused by inactivation of tumor suppressor gene APC
• There is a loss LOH (loss of Heterozygosity)
• However, most are not hereditary but more than 80% of these cancers show inactivation of both copies of the APC genes

Question 22

WHat is hereditary nonpolyposis colorectal cancer (HPNCC) ?

Answer 22

• Cancers cells are unsual
• most HPNCC cells have normal chromosme number or near normal number of chromosmes
• Colorectal cancer cells usually have multiple copies of chromosomes

Question 23

WHat are different types of cancer treament?

Answer 23

Chemotherapy drugs that treat cancer

Chemotherapy stops cell division - impact on rapidly dividing cells (cancer cells) but…..

Causing

• Loss of hair
• nausea
• anemia and immune dysfucntion

Cancer strategy = give as strong a dose as possible to kill a tumor and almost kills the patient

Question 24

What is the cause of chronic myelogenous leukemia?

Answer 24

* Translocation of 9 and 22 = phildelpha chromasome * Bcr-Abl causes it

Question 25

What BCR-Abl (this post translocation )

Answer 25

* Abl is a tyrosine kinase for cell signaling * N terminus BCR makes it hyperactive * bth are fused during translocation * BCR-ABl makes a highly active tyrosine kinase that highly xpressed * causes cell proliferation = cancer CML * treatment is GleevecL inhibts tyrosine kinase activity * causes disappearance of phildelphia chromosome in \>80% of patients

Question 26

Question 27

What is the next step in cancer research?

Answer 27

* Personalized medicine * Cancers can be extremely heterogenous so how do we treat * red = tumor RNA * Green = normal tissue RNA * Gene expression profile of a cancer can be analyzed by microarray to identify disrefulated cancer crital genes. * custom given treatments can be selected to target specific dysregulated cancer critical proteins

Question 28

What is angiogensis therapy?

Answer 28

The idea that cancerous tumor require formation of new blood vessles to go through metastasis via angiogenesis, Iwe can starve the stare the tu ors by prevent angiogensis

Question 29

Which genes in lecture are onco or tumor repressors?

Answer 29

* Oncogenes * CDK * RAS * MYC * BLC2 * Tumor repressors * Rb * CKI (P21 and P16) * p53