Cancer Genes Flashcards
Cancer Genes
Proto-oncogene: A gene that normally functions to control cell division and may become a cancer gene (oncogene) by mutation
Oncogene: A gene that induces or continues uncontrolled cell proliferation, acts in an autosomal dominant fashion
Oncogene Addiction
Oncogene Addiction : The continued activity of the specific over expressed oncogene is necessary for the maintenance of malignant phenotype.
1. Transgenic mouse is over expressed with myc oncogene, which induces the formation of malignant osteogenic sarcoma.
2. Loss of over expression leads to differentiation and the formation of normal osteocytes.
3. Similarly conditional activation of Bcr-Abl gene in transgenic mouse resulted in development of leukemia and subsequent deactivation leads to apoptosis of cancer cells.
4. On the contrary it is not always necessary that continued over expression is required for maintenance of malignant phenotype.
5. Over expressed oncogenes shows their effects by causing genomic instability.
6. A subset of a c-Myc dependent tumor cells escape Myc dependence by activating endogenous ras oncogenes.
Altered Gene Function
Base substitutions
K-ras : Cys-12(mutated) Ala-59 Gln-61 = lung carcinoma
Altered regulation
Burkitt lymphoma : c-myc1
t(8;14) 80% of cases
t(8;22) 15% of cases
t(2;8) 5% of cases
1c-myc is translocated to the IgG locus, which results in its activated expression
Chronic myelogenous Leukaemia : bcr-abl2
t(9;22) 90-95% of cases
2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase
Translocation results in “Philadelphia chromosome”
Results in fusion of BCR (multi-domain signaling protein) and Abl (non-receptor tyrosine kinase )
Imatinib (Gleevec, STI-571)
Indications: CML, gastrointestinal stromal tumors(GISTs)
Mechanism: competitive inhibitor of tyrosine kinases
Viral Genes
cellular proto-oncogenes that have been captured by retroviruses and have been mutated in the process (and “activated”)
Viral insertion
adenovirus ds-DNA : E1A & E1B
virus-specific genes that behave like cellular proto-oncogenes that have been mutated to oncogenes (i.e., “activated”)
Viral insertion
Kirsten murine sarcoma : v-K-ras -> c-K-ras (K-ras
MicroRNA
MicroRNA Genes (encode for single strand RNA of about 21-23 nucleotides)
Deletion or downregulation of microRNA (miR)-15a/miR-16-1 cluster, located at chromosome 13q14.3 and directly involved in the regulation of BCL2 and MCL1 expression, represent an early event in the pathogenesis of CLL.
During the evolution of malignant clones, other microRNAs (miRs) can be deleted (such as miR-29) or overexpressed (such as miR-155), contributing to the aggressiveness of B-cell CLL.
Such abnormalities can influence the expression of other protein-coding genes (PCGs), as TCL1 oncogene, directly regulated by miR-29 and miR-181, or affect other noncoding RNAs(ncRNAs).
The consequences of this steady accumulation of abnormalities are represented by the reduction of apoptosis and the induction of survival and proliferation of malignant B cells, leading to the evolution of more aggressive clones.
Members of the miR-29 family, lost in AML and in other tumor types as lung cancer, have also been shown to directly target MCL1 and DNMT3A and B.
Ras
Ras family proteins
the c-ras family contains three genes: H-ras, K-ras, and N-ras
the Ras proteins encoded by these genes are small G-proteins
the proteins transmit growth signals from cell surface receptors
the Ras proteins are activated by binding GTP
the proteins are inactivated by GTP to GDP hydrolysis
mutations in the c-ras genes inactivate the Ras GTPase
mutated Ras proteins are constitutively active
constitutively active Ras proteins result in uncontrolled cell growth
Retinoblastoma
Retinoblastoma
1 in 20,000 children
Most common eye tumor in children
Occurs in heritable and non-heritable forms
Identifying at-risk infants substantially reduces morbidity and mortality
Rb
Growth suppression
E2F is a transcription factor that mediates growth-dependent activation of genes required to make the transition into and through S phase
Rb binds and inactivates E2F under conditions of growth suppression
There are several ways to alleviate growth suppression resulting in controlled or uncontrolled cell growth:
G1 phase phosphorylation releases E2F
Adenovirus E1A oncoprotein binding releases E2F
Gene mutation affecting binding pocket releases E2F
P53
p53 is the “guardian of the genome” – Li-Fraumeni syndrome
*p53 is frequently found mutated in human tumors
* the p53 protein functions as a transcription factor that regulates cell-cycle and DNA repair genes
* UV irradiation causes cell-cycle arrest in G1 that is dependent on p53; cells that contain a mutated p53 cannot arrest and go into S phase and replicate damaged DNA
* p53 loss-of-function mutations result in the replication of cells with damaged DNA and to the further accumulation of other mutations affecting oncogenes and tumor suppressor genes, and to an increased likelihood of cancer
Gene Therapy
Gene Therapy
Gene therapy is the insertion of genes into an individual’s cells and tissues to treat a disease, such as a hereditary disease in which a deleterious mutant allele is replaced with a functional one.
Basic process for gene therapy:
A vector delivers the therapeutic gene into a patient’s target cell
The target cells become infected with the viral vector.
The vector’s genetic material is inserted into the target cell.
Functional proteins are created from the therapeutic gene causing the cell to return to a normal state.
Gene Therapy Uses
Uses of gene therapy
Replace missing or defective genes;
Deliver genes that speed the destruction of cancer cells;
Supply genes that cause cancer cells to revert back to normal cells;
Deliver bacterial or viral genes as a form of vaccination;
Provide genes that promote or impede the growth of new tissue; and;
Deliver genes that stimulate the healing of damaged tissue.
Types of Gene Therapy
Types of Gene Therapy
Gene therapy can target somatic (body cells) or germline (sperm cells, ova, stem cell precursors of sperm and ova) cells.
In somatic gene therapy the recipient’s genome is changed, but the change is not passed on to the next generation; whereas with germ line gene therapy the newly introduced gene is passed on to the offspring.
Most gene therapy treatments in humans has been directed at somatic cells.
Germline gene therapy remains controversial.
For germline gene therapy, the introduced gene must be incorporated into the chromosomes by genetic recombination.
Ex Vivo
ex vivo: cells are modified outside the body and then transplanted back again.
Usually done with blood cells because they are easiest to remove and return.
Sickle cell anemia
In Vivo
in vivo: genes are changed in cells still in the body.
In vivo techniques usually utilize viral vectors
Virus = carrier of desired gene (vector).
Ideal vector characteristics:
Insert size: one or more genes.
Targeted: limited to a cell type.
No immune response.
Stable: not mutated.
Production: easy to produce high concentrations
Can be Regulated: produce enough protein to cause an effect.
Virus genome is manipulated to remove disease-causing genes and introduce therapeutic genes.
Viral methods have proved to be the most efficient to date.
Many viral vectors can stable integrate the desired gene into the target cell’s genome.
Infusion of adenoviral vectors into the trachea and bronchi of cystic fibrosis patients.
Injection of a tumor mass with a vector carrying the gene for a cytokine or toxin.
Injection of a dystrophin gene directly into the muscle of muscular dystrophy patients.
Recombination based approaches in vivo are uncommon as most DNA constructs have a very low probability.
