Pathoma Chapter 3B Flashcards
Proto-oncogenes are essential to?
cell growth and differentiation;
mutations of proto-oncogenes form
oncogenes that lead to unregulated cellular growth.
Categories of oncogenes include
growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators
Growth factors induce
cellular growth (e.g PDGFB in astrocytoma),
Growth factor receptors
mediate signals from growth factors (e.g. ERBB2 HER2/neu in breast cancer).
What do signal tranducers do?
Relay receptor activation to the nucleus (eg. ras)
Ras is associated with
growth factor receptors in an inactive GDP-bound state.
Aflatoxins
Hepatocellular carcinoma Derived from Aspergillus, which can contaminate stored grains
Alkylating agents
leukemia/lymphoma side effect of chemotherapy
Alcohol
Squamous cell carcinoma of oropharynx and upper esophagus, pancreatic carcinoma, and hepatocellular carcinoma
Arsenic
Squamous cell carcinoma of skin, lung cancer, and angiosarcoma of liver. Arsenic is present in cigarette smoke.
Asbestos
Lung carcinoma and mesothelioma. Exposure to asbestos is more likely to lead to lung cancer than mesothelioma.
Cigarette smoke
Carcinoma of oropharynx, esophagus, lung, kidney, and bladder. Most common carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogenic.
Nitrosamines
Stomach carcinoma, Found in smoked foods, responsible for high rate of stomach carcinoma in japan
Naplithylamine
Urothelial carcinoma of bladder. Derived from cigarette smoke
Vinyl chloride
Angiosarcoma of liver, occupational exposure; used to make polyvinyl chlurkle (PVC) for use in pipes
Nickel, chromium, beryllium, or silica
Lung carcinoma Occupational exposure
Oncogenic viruses
EBV, HHV-8, HBV and HCV, HTLV-1, High-risk HPV
EBV
Nasopharyngeal carcinoma, Burkitt lymphoma and CNS lymphoma in AIDS
HHV-8
Kaposi sarcoma
HBV and HCV
Hepatocellular carcinoma
HTLV-1
Adult T-cell leukemia/lymphoma
High-risk HPV (e.g. subtypes 16, 18, 31, 33)
Squamous cell carcinoma of vulva, vagina, anus, and cervix; adenocarcinoma of cervix
Ionizing radiation
(nuclear reactor accidents and radiotherapy) AML, CML and papillary carcinoma of the thyroid. Generates hydroxyl free radicals.
Non Ionizing (UVB sunlight is most common source)
Basal cell carcinoma, squamous cell carcinoma, and melanoma of skin
Non Ionizing radiation results in?
formation of pyrimidine dimers in DNA, which are normally excised by restriction endonuclease
Ras Receptor binding causes
GDP to be replaced with GTP, activating ras.
What does activated ras do?
sends growth signals to the nucleus
How is Ras deactivated?
inactivates itself by cleaving GTP to GDP; this is augmented by GTPase activating protein
Mutated ras
inhibits the activity of GTPase activating protein. This prolongs the activated state of ras, resulting in increased growth signals.
Cell cycle regulators mediate what?
progression through the cell cycle (e.g. cyclin and cyclin-dependent kinase).
Cyclins and cyclin-dependent kinases (CDKs) do what?
form a complex which phosphorylates proteins that drive the cell through the cell cycle.
The cyclin D / CDK4 complex does what?
phosphorylates the retinoblastoma protein, which promotes progression through the G-S checkpoint
What do tumor supressor genes do?
Regulate cell growth decreasing (suppress) the risk of tumor formation;
What are some classic examples of tumor supressor genes?
p53 and Rb (retinoblastoma)
What does p53 regulate?
progression of the cell cycle from G to S phase
In response to DNA damage, what does p53 do?
slows the cell cycle and upregulales DNA repair enzymes.
PDGFB
Platelet-derived growth factor, overexpression, autocrine loop, astrocytoma
FRBB2 [HER2f neu]
Epidermal growth factor receptor, Amplification mechanism, Subset of breast carcinomas
RET
Neural growth factor receptor, Point mutation MEN 2A, MEN 2B and sporadic medullary carcinoma of thyroid
KIT
Stem cell growth factor receptor, Point mutation, Gastrointestinal stromal tumor
RAS gene family
GTP-binding protein, Point mutation, Carcinomas, melanoma, and lymphoma
ABL
Tyrosine kinase T(9;22) with BCR CML and some types of ALL
What are the nuclear regulators?
C-MYC, N-MYC, L-MYC
c-MYC
Transcription factor, t(8;I4) involving IgH, Burkitt lymphoma
N-MYC
Transcription factor, Amplification, Neuroblastoma
L-MYC
Transcription factor, Amplification, Lung carcinoma (small cell)
CCND1 (cyclin D1)
Cyclin t(8;14) involving IgH, Mantle cell lymphoma
If DNA repair is not possible, what does p53 do?
induces apoptosis.
How does p53 induce apoptosis?
upregulates BAX, which disrupts Bcl2 leading to cytochrome c leaks from the mitochondria activating apoptosis
