EXAM 2 - Session 21: Cancer Oncogenes and Tumor Suppressor Genes Flashcards
What happens when tumor (growth) suppressor genes are present in normal cells? What happens when they are mutated?
Normal function: tumor (growth) suppressor genes are added to cancer cells in petri dish and get its encoded protein expressed –> result: inhibits/slows growth of cancer cells
Mutated tumor suppressor: loss of gene in normal cells –> result: uncontrolled growth
What is the function of proto-oncogenes on normal cells? What about oncogenes?
Proto-oncogenes: add normal proto-oncogenes to normal cells –> ecoded protein is expressed –> result: limited growth increase
Oncogenes: add mutated oncogene to normal cells –> result: uncontrolled growth
List the 5 broad categories of tumor suppressor genes defined by protein function.
multiple functions of any ONE protein may classify it to multiple categories
- control general progression of cell cycle (Rb, p53)
- function as control proteins of specific cell cycle checkpoints – G1: sufficient cell growth;* G2*: completed c’some replication; Metaphase: c’somes attached to mitotic spindle (BRCA, p53)
(can control replication by stopping replication at cell cycle checkpoints) - transfer or coordinate signals from cell membrane receptors and cytoplasmic enzymes that inhibit cell proliferation (APC)
- regulate expression of apoptosis-related proteins (p53 –> Bcl and Bax)
- aid repair of DNA either directly (enzymatically), scaffold recruitment of repair proteins, or halt cell cycle to allow time for repair (BRCA, p53)
Describe tumor suppressor: Rb - Retinoblastoma.
tumor: overgrowth of retinal cells
Lost of Rb function due to gene mutation
* BOTH alleles MUST be LOST or MUTATED –> lost of gene function
* 1 normal, 1 mutated gene –> protein sufficient for normal control of cell cycle (doesn’t cause tumor, but increases risk since second allele can get mutated
Describe the normal function of Rb on cell cycling (CC)
Rb is located in all cells (not just retinal)
* Rb normal protein function: stabilizes p27 (CC inhibitor) –> longer p27 half-life
* binds to some transcription factors ad cyclin/CDKs –> lessen CC activity
Describe the function of mutated Rb on cell cycling (CC)
- p27 is less stable –> makes cyclin/CDK more active –> CC progression
- binds to and inactivates PRO-apoptotic proteins –> less induced cell death
Describe the normal function of p53 in normal cells.
p53 is a CC inhibitor - tumor suppressor
* inhibits CC progression
* p53 function is blocked by MDM2 protein
* hi MDM2 –> progression of CC
* low MDM2 –> stopping CC
Describe the function of mutant p53 on cancer cells.
- Some cancer cells have p53 that is non-functional (no brake for CC)
- other cancer cells have normal p53 but high MDM2 –> blocks p53 function
If p53 inhibits the CC and if interaction with MDM2 blocks p53 function, then…
then preventing MDM2-p53 interaction should release p53 –> p53 will be able to inhibit CC.
Describe the mode of action for a drug that prevents MDM2-p53 interaction.
Small molecule drug competitively binds to MDM2 at the site where p53 usually binds.
* p53 is freed and can function normally (inhibit CC)
Describe the mode of action for a drug that prevents MDM2-p53 interaction.
Small molecule drug competitively binds to MDM2 at the site where p53 usually binds.
* p53 is freed and can function normally (inhibit CC)
In breast cancer, what are the two BRCA susceptibility genes? Explain what mutations of BRCA genes mean.
BRCA1 on c’some 17
BRCA2 on c’some 13
* mutation in either c’some increases risk of breast cancer
* one mutation in either gene is NOT 100% causative of cancer –> but increases risk to 80%
What is the normal function of BRCA proteins? What happens when their mutated?
Help repair breaks in DNA by acting as scaffold for repair enzymes
* mutations disable repair –> lead to errors in DNA sequence –> cancer
How do BRCA tumor suppressors facilitate DNA repair?
- BRCA2 recruits Rad51 to the double strand break
- Rad51 promotes alignment with homologous c’some
- Homologous c’some is used as a template to repair missing sequence at double-stranded break
- failure = activation of oncogenes (uncontrolled replication)
List the 5 broad categories of proto-oncogenes as defined by protein function.
multiple functions of any ONE protein can classify it to multiple categories
1. function as growth factors
(mutation leading to too much GF protein –> excess cell growth
2. serve as receptors for growth factors
(mutation may make them active –> no GF needed or excess response to normal low level of GF)
3. serve as signal transducers carrying signal from cell membrane to nucleus
(mtn may make them active without upstream/incoming signal)
4. function as transcription factors
(mtn –> excess or inaccurate gene transcription)
5. Regulate apoptosis
(mtn –> cell resistant to apoptotic signal –> doesn’t kill cancer cells)
Describe the characteristics of activated (mutated) src oncogenes.
Mutated src gene promoter –> very high expression of normal src kinase
Mutated src gene coding sequence –> very high kinase activity
- excess phosphorylation
- excess CC promotion
Describe the characteristics of Abelson (abl) proto-oncogene activation to oncogene form.
abl mutation specific to chronic myeloid leukemia (CML)
* philadelphia (Ph) c’some provides marker of cells clonally derived from cancer stem cells
* brings together BCR on c’some 22 (encodes scaffold protein; coordinates protein interactions) and ABL on c’some 9 (enzyme with low kinase activity)
* result: BCR-ABL gene –> produces hybrid protein with high kinase activity –> activates CC-promoting signals
