Lecture 12: Biochemistry of Cancer Flashcards
What chromosome can one find the Rb gene?
Chromosome 13
An individual with a deletion of one Rb+ allele is said to be _____.
Predisposed to developing retinoblastoma.
Loss of both Rb+ alleles…
…induces tumor formation.
True or false?
Loss of the Rb gene is found only in retinoblastoma cases.
False.
The Rb gene is frequently missing in several other types of cancer as well.
What are the two forms of retinoblastoma?
- Hereditary.
2. Sporadic.
E2F
A transcription factor that helps transcribe genes whose products are required for the S-phase of the cell cycle.
pRB
The protein product of the Rb gene.
When UN-phosphorylated, it is bound to the transcription factor E2F.
Phosphorylated pRB
Dissociates from E2F, allowing it to exert its effects on the transcription of S-phase-dependent proteins.
Unphosphorylated pRB
Is bound to E2F, keeping it from exerting its effects on the transcription of S-phase-dependent proteins.
Cyclin D and Cyclin E
Bind with cyclin-dependent kinase (CDK) to phosphorylate pRB.
What happens in the absence of pRB?
E2F is left unbound, therefore exerting its effects on the up-regulation of S-phase dependent proteins.
Cells, even with damaged DNA, can continue to replicate.
Many anti-proliferative signals are funneled through which protein?
pRB.
Which protein is the substrate for many “stress-related” phosphorylation events?
p53.
RE
Response element. Usually in reference to the regulatory region where p53 binds.
Once DNA damage is detected (or an oncogene is expressed), what protein is activated?
p53.
What are the two outcomes after p53 has been activated?
- Apoptosis
2. Activation of p21
p21 (two functions)
Activated by p53 when DNA damage is detected.
- Inhibits cyclin/CDK complexes, which in turn halt the cell cycle.
- Binds to PCNA (clamp), inhibiting progression of replication forks.
Many cancer cells do not undergo apoptosis due to what is thought to be an absence of what protein?
p53.
What type of cancer(s) does the following tumor suppressor, when dysfunctional, cause?
RB
Retinoblastoma
What type of cancer(s) does the following tumor suppressor, when dysfunctional, cause?
p53
- Sarcomas
2. Carcinomas
What type of cancer(s) does the following tumor suppressor, when dysfunctional, cause?
NF1
Neuroblastoma
What type of cancer(s) does the following tumor suppressor, when dysfunctional, cause?
APC
- Colon
2. Stomach
What type of cancer(s) does the following tumor suppressor, when dysfunctional, cause?
BRCA 1
Breast Cancer
In regards to an oncogene, how many of the cell’s copies need to be altered?
Only one. This is a “dominant effect.”
Signal Transduction
The movement of signals from outside the cell to the nucleus.
What does signal transduction have to do with cancer?
Tumor cells generate many of their own growth signals.
What is sis and where was it originally discovered?
Simian sarcoma oncogene; discovered in a transforming retrovirus.
What does sis encode?
Part of the PDGF (a tyrosine kinase), which is able to induce signal transduction.
What is EGF and it’s role in cancer?
Epidermal growth factor. Mutant forms of the EGF receptor are known to constantly stimulate growth, even in the absence of EGF.
What are family members of EGF?
Erb/HER2.
What is Ras?
A signaling molecule that is important in signal transduction to the nucleus.
When GTP is bound to Ras, it is said to be ____.
Active.
When GDP is bound to Ras, it is said to be ____.
Inactive.
What is GAP?
GTPase Activating Protein
What does the NF1 gene encode?
NF1 encodes a protein called neurofibromin, which contains a GAP domain.
Describe what happens in NF1.
Neurofibromin is altered, which results in a defective GAP domain that is supposed to deactivate Ras and its signaling pathway to the nucleus.
What three important transcription factors interact with the signal transduction pathway?
FOS, JUN, and MYC.
How are FOS and JUN related?
They need to bind to one another to form AP1, which can then bind to DNA.
AP1
A heterodimer of FOS and JUN.
How are FOS and JUN related to cancer?
Over-expression of these two factors can result in elevated transcription of growth-dependent genes, and ultimately, continuous (instead of transient) cell growth.
Neurofibromatosis
Neuofibromas appear on the skin, also called cafe au lait spots.
What is Myc?
Myc is a gene that encodes a transcription factor that regulates the expression of 15% of all genes.
What are two roles of MYC?
MYC binds to enhancer sequences (e-boxes) and recruits histone acetyltransferases (HATs).
What occurs as a result of certain mutated forms of Myc?
Up-regulation of genes, some of which are involved in cell proliferation.
What is the cytogenetic etiology of Burkitt’s lymphoma?
A translocation between chromosome 8 and one of three chromosome (2, 14, and 22) that encode antibody molecules.
When translocated, the Myc gene is constitutively (constantly, regardless of need/demand) expressed.
How does a DNA tumor virus work?
It sequesters Rb and p53, causing cell proliferation by freeing cell proliferation transcription factors.
What are the six hallmarks of cancer?
- Evading apoptosis.
- Self-sufficiency in growth signals.
- Insensitivity to anti-growth signals.
- Sustained angiogenesis.
- Limitless replicative potential.
- Tissue invasion and metastasis.
Familial APC
Familial adenomatous polyposis coli
