Cancer Flashcards
What are the 6 capabilities that a normal cell must acquire to be transformed into an invasive tumor?
1) self sufficiency in growth signals
- oncogenes send inappropriate growth signals
2) insensitivity to antigrowth signals
- loss of tumor suppressor function
3) evading apoptosis
4) limitless replicative potential
- reactivation of telomerase
5) sustained angiogenesis
6) tissue invasion and metastasis
What are proto-oncogenes?
- genes associated with control of cell division
- act to promote cell growth
What are tumor suppressor genes?
function to inhibit cell growth and division
What does loss of function to tumor suppressor genes do?
inappropriate cell growth and division will occur
What are caretaker genes?
act to protect the integrity of the genome such as DNA repair enzymes
What are oncogenes?
- mutated form of proto-oncogene
- excessively active in growth promotion
What are ErbB1 and HER2?
proto-oncogenes
Which does this occur to?
mutation that truncates the protein and removes the extracellular domain that normally binds to its ligand, resulting in the receptor to be constantly on
ErbB1
Which does this occur to?
point mutation in region of the protein that spans the plasma membrane, which allows the receptor to dimerize and autophosphorylate, causing it to be always on
HER2
- example of overproduction of a normal protein which can lead to tumor formation
What happens when Ras is constantly on?
Ras is G-Protein that activates Raf which ultimately leads to the activation of Map Kinase that promotes transcription
What are c-Fos and c-Myc?
proto-oncogenes
transcription factors
What happens when c-Fos and c-Myc are converted to oncogenes?
- normally they are unstable and are degraded rapidly after they assert their effects on transcription
- when they become on-cogenes they become stable and continue to assert their affects as transcription factors
What disease results from inappropriate Myc activity?
- translocation has moved the c-Myc gene from its normal position on chromosome 8 to chromosome 14
- the new location allows for continuous expression of myc
Burkitt’s Lymphoma
- B cells become cancerous
What causes instability of p53?
the protein Mdm2 associates with p53, causing it to be ubiquitinated and degraded (normal)
What happens to p53 when there’s DNA damage?
ATM/ATR causes displacement of Mdm2 from p53, preventing it from being degraded.
p53 hen activates p21CIP1 (CDK inhibitor) which leads arrest of cell cycle. this allows the cell time to repair the damaged DNA or mark for apoptosis if it can’t be repaired
What’s the significance of the structure of p53?
it is a homotetramer and is only functional as a homotetramer
- any mutations of any of the proteins that make up the tetramer renders the protein inactive
What is the cause of Li-Fraumeni Syndrome?
- inheritance of the mutated gene that encodes for p53
- presence of multiple tumors within an individual and multiple affected family members as well
HPV produces two inhibitory proteins, what are they and what do they do?
E6 - binds to p53 and marks it for ubiquitination and degradation
E7 - binds to Rb, releasing E2F to influence cell proliferation
What is the function of neurofibromin, encoded by NF1 gene?
accelerates the rate Ras hydrolyzes bound GTP and return back to GDP-bound state, keeps the signal short
What happens when the NF1 gene is mutated?
constant activation of downstream components leading to increased cell proliferation
What is neurofiromatosis?
tumors of sheath cells that surround nerves
Why are BRCA1 and BRCA2 important?
repair of double-stranded DNA breaks
What is the breakage/ fusion/ bridge cycle?
- fusion can occur when telomeres are lost
- bridge is formed between the sister chromatids
- breakage occurs when anaphase happen, pulling at points that are not at the fusion points
- these steps lead to chromosome instability
What is hypoxia?
pro-angiogenetic factors
- stimulates oxygen-sensitive transcription factors
What is HIF-1alpha beta?
hypoxia-inducible factor
- regulates expression of multiple genes
Under normoxia, what happens to HIF-1alpha?
it is hydroxylated by proline hydroxylase and serves to recruit E3 ubiquitin ligase, leading to its degradation
Under anoxia, what happens to HIF-1alpha?
it is not hydroxylated, instead it binds with HIF-1beta and activates transcription of genes that promote angiogenesis (ex. VEGF)
What does vascular endothelial growth factor (VEGF) do?
devlopement of an angiogenic gradien, stimulating the growth of new blood vessels
What does beta-catenin do?
translocate into the nucleus and stimulates transcription of Myc and cyclin D, leading to cell proliferation
What pathway is associated with beta-catenin?
WNT signaling pathway
In absence of WNT signal, what occurs in the signaling pathway?
tumor suppresor APC binds to beta-catenin and other proteins (destruction complex), leading to degradation of beta-catenin
What occurs in the presence of WNT signal?
beta catenin does not get degraded and enters the nucleus
What disease is associated with mutations to APC gene?
FAP (familial adenomatous polyposis)
- rare disease but colon cancer is not and loss of APC is associated with colon cancer development
What genes are generally mutated in HNPCC or Lynch Syndrome?
MSH 2 - identifies DNA mismatch
MLH 1 - participates in repair process
Imatinib
effective inhibitor of Bcr-Abl (Philadelphia chromosome)
- treatment for chronic myeloid leukemia
What is the target of trastuzumab (Herceptin) used in the treatment of some breast cancers?
extracellular domain of HER2/Neu
- it has very potent anti-tumor effects
