Chapter 4: Growth factor signaling and oncogenes (Book 4.2) Flashcards
There are two major classifications of mutated genes that contribute to carcinogenesis. Those are.. (also think about their general description)?
Oncogenes (gene has mutated, what causes an increase in product produced and therefore acts in a dominant manner) and tumor suppressor genes (mutation has caused loss of function).
In the book there’s this block of text about the discovery of oncogenes through the use of viruses in animals. I will not discuss this part here. Just know that the early observation that viruses could cuase cancer in animals, lead to the discovery of oncogenes.
Okay
Describe the life cycle of retroviruses
They inject their infectious RNA into a host cell. Viral RNA is reverse-transcribed into DNA and is then called a provirus. The provirus is randomly integrated into the host genome. Translation of the provirus in the genome produces the viral proteins for the synthesis of new viral particles.
How are retroviruses involved in the formation of oncogenes?
A virus can acquire fragments of genes from the host at integration sites and this process may result in the creation of oncogenes. (Viral DNA may also me translated as a fusion protein, in conjunction with cellular DNA, resulting in a novel fusion protein, or host genes may fall under the regulation of viral regulatory sequences).
Just know that the name for a proto-oncogene as a normal cellular (c) gene is referred to as c-src. The name for an oncogene with an altered form transduced by retroviruses (v) is referred to as v-src.
Okay
There’s a viral oncogene, v-sis. Its protein product was cytoplasmic and was found to be a truncated version of a growth factor normally secreted by platelets, called platelet-derived growth factor (PDGF). It’s normal role is in e.g. would healing. What’s significant about the oncogenic form?
-It’s aberrant location (cytoplasmic rather than secreted). - The subsequent activation of the PDGF signal pathway at inappropriate times, leading to unregulated growth.
What oncogene was originally identified from the avian erythroblastosis leukemia virus?
The oncogene v-erbB, it is a truncated form of the epidermal growth factor receptor (EGFR) whereby the extracellular domain is deleted.
What identity belongs to the proto-oncogene that is related to the oncogene v-erbB?
The cellular gene is c-erbB and the identity of the product of the proto-oncogene is EGFR.
The mutated EGFR receptor triggers …. in the absence of EGF.
Cell division
What is another way how normal c-erbB contributes to carcinogenesis?
Increasing the amount of normal c-erbB product by gene amplification (this particularly happens in breast cancer).
What role does RET signaling have?
It plays an important role in kidney development and neuronal differentiation during embryogenesis.
What the proto-oncogene ret code for? What is its function?
It codes for another growth factor tyrosine kinase receptor that heterodimerizes with cell-surface co-receptors GFR-α1-4. This, so that the signal for glial-derived neurotrophic factor (GDNF) family ligand is transduced.
How is the signal for glial-derived neurotrophic factors (GDNF) family ligands transduced?
The ligands will not directly bind to RET, but first will form a complex with co-receptors. These recruit RET. RET then undergoes a conformational change, dimerizes and undergoes autophosphorylation.
What type of carcinoma often carries somatic chromosomal rearrangements involving the amino-terminal parts of numerous genes and the sequences of ret that code for the tyrosine kinase domain?
Papillary thyroid carcinoma
What kind of proteins results from this chromosomal rearrangements in papillary thyroid carcinoma?
A fusion protein that displays cytoplasmic kinase activity independent of GDNF signaling.
Which three familial autosomal dominant tumor syndromes are associated with germline mutations?
Multiple endocrine neoplasia 2A (MEN2A), MEN2B and familial medullary thyroid carcinoma.
What is mutated in multiple endocrine neoplasia 2A (MEN2A) and what results from this?
Mutations in conserved extracellular cysteines. This results in intermolecular disulfide bonds that cause constitutive RET dimerization and aberrant activation.
What is mutated in multiple endocrine neoplasia 2B (MEN2B) and what results from this?
As substitution mutation whereby conserved Met is replaced by Thr (Met918Thr). Conserved Met is characteristic of the substrate binding domain of the receptor tyrosine kinase. The substitution results in altered substrate acces, leading to increased kinase activity and altered substrate specificity.
Oncogenic activation of receptor tyrosine kinases occurs through specific mutations that lead to constitutive … (1), …(2), or … (3).
- tyrosine activation 2. dimerization 3. altered substrate specificity
What is the most commonly mutated oncogene in human cancers?
The ras gene.
The majority of mutation are located in codons 12, 13 and 61. What is the consequence of these mutations?
Loss of GTPase activity of the RAS protein which puts RAS in a constitutive active state due to GTPase not being able to exchange Ras bound GTP for Ras bound GDP.
Some specific mutations in the ras gene are characteristic for specific cancer. What mutation is characteristic for bladder carcinoma and what for lung cancer?
-Bladder carcinoma: G12V point mutation within codon 12 which results in the substitution of valine (GTC) for glycine (GGC). -Lung cancer: point mutation within codon 12 where cysteine gets substituted.
What is an important part of a transformation assay to demonstrate oncogenes and their genetic alterations (or in other words: on what is a transformation assay based?
Cancer cells can be distinguished from normal cells in cell culture conditions. It is based on the characteristic that cancer cells grow as foci against a monolayer of normal cells.
Name another transducer that can become oncogenic.
B-raf, oncogenic activation of B-raf is common in melanomas.
