- loss of function is associated with the Von Hippel-Lindau disease
- Product of the VHL gene is the protein pVHL.
- Function of pVHL is ubiquitylation of HIF-1α, which is one of two subunits of the HIF-1(hypoxia-inducible factor-1) transcription factor.
- Polyubiquitylation of HIF-1α leads to its degradation and therefore prevents the formation of a functional HIF-1.
- A functional HIF-1 transcription factor causes expression of genes such as VEGF, PDGF, TGF-α, which are growth promoting genes in the context of establishing new blood vessels.
- Normally, pVHL constitutively prevents HIF-1 to become active, but if the cell experiences hypoxia, pVHL fails to bind to the HIF-1α subunit and therefore an adequate stimulation of angiogenesis and erythropoiesis will establish an sufficient oxygen supply for the cells suffering hypoxia.
- If pVHL cannot form, since VHL was deactivatied by (e.g.) mutation, HIF-1α is constitutively active, which leads to an inappropriate high level of these growth factors, which will favor tumor growth.
- Loss of function can contribute to the development of Familial adenomatous polyposis (FAP)
- Together with GSK-3β and axin Apc builds the β-catenin destruction complex, which playes a key role in the wnt-signalling pathway.
- In colonic crypts, Apc negatively controls the levels of β-catenin, which governs the proliveration of the enterocytes in the crypt:
- Cells are produced at the bottom of the crypt and migrate upward to the villus.
- β-catenin levels decrease coninously from the lower crypt to the upper villus. This is because the migrating cells increase the expression of APC which, in the absence of Wnts, is able to break down β-catenin.
- The absence of β-catenin drives cells to differentiation.
- If APC is mutated and therefore not able to build the β-catenin destruction complex, β-catenin levels stay high and prevent cells from differentiation.
- Continuous proliferation and the formation of polyps is the consequence.
- Tumor Suppressor Genes are the counterpart to oncogenes.
- Inactivation of Tumor Suppressor Genes favours tumor growth.
- Cancer phenotype is recessive.
- However, If induced by viruses, cancer phenotype is dominant.
- Tumor Suppressor Genes can explain the phenomenon of familial cancer syndroms.
- Tumor Suppressor Genes may be inactivated by LOH (loss of heterozygosity / allelic deletion).
- LOH occurs at a far higher frequency that mutational alterations. That is why the loss of a TSG is more frequent than somatic mutations (10^6 for one allele, 10^12 for both at the same time).
- Tumor Suppressor Genes may be inactivated by disabling the promoter.
- In order to “find” Tumor Suppressor Genes / “find” genes that are not there in the phenotype of interest (cancer), genetic markers that are close to the gene of interest can be used:
- Restriction fragment length polymorphism: Depends first on SNPs that affect one allele but not the other and second on restriction enzymes that cleave this site.
- PCR: Also depends on SNPs that affect one allele but not the other: However, in this case there are primers used that are specific to sequences that are polymorphic.
- Tumor Suppressor Genes are either gatekeepers (direct cells through growth, division and death) or caretakers (maintenance of the genome, genomic stability).
- Examples for Tumor Suppressor Genes:
- RB: retinobastoma, osteosarcoma; transcriptional repession, control of E2Fs
- APC: familial adenomatous polyposis coli; β-catenin degradation ( see also)
- VHL: Von Hippel-Lindau disease; ubiquitin ligase
- TGFBR2: TGF-β receptor
- p16: familial melanoma; CDK inhibitor
- p14: p53 stabilizer
- NF1: neurofibromatosis type 1; Ras-GAP
- NF2: neurofibroma-position syndrome; cytoskeleton-membrane linkage
- PTEN: breast and gastrointestinal carcinomas; PIP3 phosphatase
The capacity to blunder slightly is the real marvel of DNA. Without this special attribute, we would still be anaerobic bacteria and there would be no music.
Lewis Thomas, biologist, 1979
This nicely points out the other side of the double-edged sword of genetic mutations, which often are considered to be evil without exception. In fact, the human body makes every effort to prevent them, and even will send his own cells to death without hesitation if they are affected.
But equally, every once in a while, they will give rise to new life, when they from a new organism, that has improved it’s adaptations to it’s world.
This way, genetic mutations maintain variety and richness of life.