White 7 "cancer 2" Flashcards
What are the 2 major categories of tumor suppressor genes?
- proteins that normally restrict cell growth and proliferation
- inhibit progression through the cell cycle
- receptors or components of signaling pathway that inhibit cell proliferation
- promote apoptosis - proteins that maintain the integrity of the genome
- checkpoint proteins
- ataxia telangiectasia
Describe retinoblastoma
- inherited eye cancer in children
- occurs before 2
- loss of both copies of Rb (inhibits cell division) genes lead to cell and tumor proliferation of the retina
What are the two forms of retinoblastoma?
hereditary and sporadic
40% is familial and both eyes are affected
60% is sporadic and there is no family history in which one eye is affected
Describe the hereditary form of Rb
-loss of function or deletion of 1 copy of Rb in every cell (because it is inherited)
-predisposed to be cancerous
-one good copy of Rb gene
somatic event occurs- eliminate one good copy and tumor forms
-loss of heterozygosity
Describe the sporadic form of Rb
- non-hereditary (start off with normal cells)
- non-cancerous cells are fine; no mutation of Eb
- cancerous cells have both copies of Rb mutated
Describe the two hit hypothesis
the first Rb gene obtains the mutation and then need second mutation
Describe the relationship between the Rb protein and E2F
E2F binds to promoters and DNA synthesis genes which drive the cell cycle
E2F is INHIBITED y the interaction with the Rb protein
Rb inhibits cell division-
This can lead to CANCER
Describe cancer in a non-proliferating cell
- activate CKI (p16) which stops Cdk
- Cdl-Cyclin complex will not phosphorylate Rb
- Rb binds to E2F which blocks the cell cycle
expression of the S phase gene is limited
Describe cancer in the proliferating cell
- CKI is absent so Cdk is always activated
- Idk-Cyclin complex can now phosphorylate Rb
- Rb inactive and E2F drives the S-Cdk activation by making more cyclins
Expression of S-phase genes is activated
Describe what happens when the Rb pathway includes the protooncogenes
Cdk or cyclin is overproduced
- these ^ genes can be oncogenes
- overproduction can overcome the amount of CKI’s
- phosphorylate Rb which is then not able to stop EF2
- uncontrolled cell growth
- CANCER
Describe what happens when the Rb pathway includes tumor suppressor genes
CKI or the Rb is the tumor suppressor gene
-if one is lost, then that can lead to cancer
1. no CKI-no control of Cdl-Cyclins
2. No Rb means no suppression of E2F and entry into cell division
CANCER
Describe p53
Huge tumor suppressor gene involved in 1. cell cycle arrest 2. DNA repair 3. apoptosis 4. block of angiogenesis
What happens if you lose p53?
- loss of checkpoint control in the cell cycle
- loss of cell cycle arrest in response to DNA damage
- loss of DNA repair activities
- loss of apoptosis in response to DNA damage
Describe p53 as a gene regulatory protein
- stimulates transcription of gene encoding CKI called p21 which stops the cell cycle
- activates expression of pro-apoptotic proteins BH123 and BH-3 only
What happens if a viral DNA fragment is accidentally integrated into the host chromosome?
MALIGNANCY
Which viral proteins (papilloma) cause malignancy and which genes do they bind to?
E6 and E7
2 genes are Rb and p53
cells can replicate in an uncontrolled manner
Describe the activation of proliferation by DNA Tumor viruses in a NORMAL cell
- Rb is bound to E2F protein to inactivate transcription of cyclins and the production of G1/S-Cdk
- p53 induces the expression of p21 which prevents the activity of the Cdks in the cell cycle
CELL PROLIFERATION is blocked
Describe the activation of proliferation by DNA Tumor Versus in a TUMOR cell
- viral protein E7 binds to Rb and so E2F can cause over expression of G1/Cdk and S-Cdk cells grow and divide
- viral protein E6 binds to p53 and inactivates it so CKI is no produced and Cdk’s act uncontrollably
- cell proliferation is ACTIVATED by the DNA virus–> CANCER
Describe metastasis in terns of the escape from the parent tissue
- Local invasiveness
2. Only a few cells will be able to escape from the parent tissue
Describe metastasis in terms of the travel through the circulation
INCLUDES: survival in the circulation, arrest in the capillary or other small vessel and exit into the remote tissue or organ
- initial entry is into the blood or lymphatic vessels is facilitated by angiogenesis
- most cancer cells have acquired this ability before becoming invasive through mutations that control apoptosis
Describe metastasis in terms of colonization of remote site
INCLUDES
survival of the cells in foreign tissue, initial growth of cells in the foreign tissue, and the persistence of growth
- Some cells may die after entering a foreign tissue
- only a few cells can hang out and cause malignancy
What is the most effective way in preventing and curing colon cancer?
Early detection
Describe colorectal cancer
- arises in the epithelial lining of the large intestine
- renewal from stem cells; highly organized epithelium in large intestine
- mutations that disrupt organization signals begin the tumor progression for cancer
What is a polyp?
precursor of colorectal cancer
slow disease progression
IF IT IS LEFT ALONE-> colon cancer
Describe the various mutations that lead to colon cancer
60% is an inactivation of p53
40% have a point mutation in K-Ras
Describe hereditary colon cancer (FAP)
starts with familial adenomatous polyposis coli (FAP)
there are hundreds of polyps and at least one will become malignant
usually only one copy of Apc has a mutation or inactivation; LOH (loss of heterozygosity)
Describe hereditary non-polyposis colorectal character
-cells are unusual
Have normal or near normal levels of chromosomes
Describe the genomic instability in colon cancer
colorectal cancer has a chromosomal mess with abnormalities such as translocations, deletions, and abnormal numbers of certain chromosomes
Describe chemotherapy
drugs that treat cancer
stop cell division
Want to give as strong of a dose to kill the tumor but not kill the patient
Describe Bcr-Abl
combined during chromosomal translocation
Abl is a tyrosine kinase for cell signaling
the N terminus of Bcr makes it hyperactive
highly active tyrosine kinase
highly expressed
leads to cell proliferation and causes cancer CML
How is the Bcr-Abl treated?
Gleevec which inhibits the tyrosine kinase
disappearance of Philadelphia chromosome
Gleevec takes place of ATP on Bcr-Abl
