FusionofportionsoftheABL tyrosinekinasegeneandtheBCR proteingene,creatingaBCR-ABL fusiongeneencodingaconstitutivelyactivetyrosinekinase,incertainleukemias
RAScommonlyismutatedinhumancancersandnormallyflipsbetweenrestingGDP-boundstateandactiveGTP-boundstate;mutationsblockhydrolysisofGTPtoGDP,leadingtouncheckedsignaling
ComplexesofcyclinswithCDKsdrivethecellcyclebyphosphorylatingvarioussubstratesandnormallyarecontrolledbyCDKinhibitors.Mutationsingenesencodingcyclins,CDKs,andCDKinhibitorsresultinuncontrolledcellcycleprogressionandarefoundinawidevarietyofcancersincludingmelanomasandbrain,lung,andpancreaticcancers.
InsensitivitytoGrowthInhibitorySignals:TumorSuppressorGenes
Isaac Newton theorized that every action has an equal and opposite reaction. Although Newton was not a cancer biologist, his formulation holds true for cell growth.
Whereas oncogenes encode proteins that promote cell growth, the products of tumor suppressor genes apply brakes to cell proliferation. Disruption of such genes renders cells refractory to growth inhibition and mimics the growth-promoting effects of oncogenes. The following discussion describes tumor suppressor genes, their products, and possible mechanisms by which loss of their function contributes to unregulated cell growth.
In principle, anti-growth signals can prevent cell proliferation by several complementary mechanisms. The signal may cause dividing cells to enter G0 (quiescence), where they remain until external cues prod their reentry into the proliferative pool. Alternatively, the cells may enter a post-mitotic, differentiated pool and lose replicative potential. Nonreplicative senescence, alluded to earlier, is another mechanism of escape from sustained cell growth. And, as a last-ditch effort, the cells may be programmed for death by apoptosis. As we will see, tumor suppressor genes have all these “tricks” in their toolbox designed to halt wayward cells from becoming malignant.
RB: Governor of the Cell Cycle
RB, a key negative regulator of the cell cycle, is directly or indirectly inactivated in most human cancers. The http://ebooksmedicine.net retinoblastoma gene (RB) was the first tumor suppressor gene to be discovered and is now considered the prototype of this family of cancer genes. As with many advances in medicine, the discovery of tumor suppressor genes was accomplished by the study of a rare disease—in this case, retinoblastoma, an uncommon childhood tumor. Approximately 60% of retinoblastomas are sporadic, while the remaining ones are familial, the predisposition to develop the tumor being transmitted as an autosomal dominant trait. To account for the sporadic and familial occurrence of an identical tumor, Knudson, in 1974, proposed his now famous two-hit hypothesis, which in molecular terms can be stated as follows:
Two mutations (hits) are required to produce retinoblastoma. These involve the RB gene, which has been mapped to chromosomal locus 13q14. Both of the normal alleles of the RB locus must be inactivated (hence the two hits) for the development of retinoblastoma (
Fig. 6.19
In familial cases, children inherit one defective copy of the RB gene in the germ line; the other copy is normal.
Retinoblastoma develops when the normal RB gene is lost in retinoblasts as a result of somatic mutation. Because in retinoblastoma families a single germ line mutation is sufficient to transmit disease risk, the trait has an autosomal dominant inheritance pattern.
• In sporadic cases, both normal RB alleles are lost by somatic mutation in one of the retinoblasts. The end result is the same: a retinal cell that has lost both of the normal copies of the RB gene becomes cancerous.