Часть 2 (1121000), страница 74
Текст из файла (страница 74)
Loss-of-function mutationsin this pathway contribute to the development of several types of human cancers. The receptor TGFB-RII, for example, is mutated in some cancers of thecolon, as is Smad4-a key intracellular signaling protein in the pathway-whichis also often inactivated in cancersof the pancreasand some other organs.Thesefindings reflect the normal function of the TGFBpathway in restricting cell proIiferation (seeFigure 23-26).Not surprisingly, mutations that directly affect the central cell-cycle control system feature prominently in many cancers.The tumor suppressorprotein Rb, discussedearlier, controls a key point at which cells decide to enterthe cell cycle and replicate their DNA.
Rb serves as a brake that restricts entryinto S phase by binding to and inhibiting gene regulatory proteins of the E2Ffamily, which are needed to transcribe genes that encode proteins required forentrance into S phase. Normall-v,this inhibition by Rb is relieved at the appropriate time by the phosphorylation of Rb by various cyclin-dependent kinases(Cdks),which cause Rb to release its inhibitory grip on the E2F proteins (disc u s s e di n C h a p t e rl 7 ) .Many cancer cells proliferate inappropriately by eliminating Rb entirely, aswe have already seen. Others achieve the same effect by acquiring mutationsthat alter other components of the Rb regulatory pathway (Figure 20-38). Innormal cells, a complex of cyclin D and the cyclin-dependent kinase Cdk4 (GrCdk) is responsible for phosphorylating Rb so as to allow progress through thecycle (seeFigure 17-62 andTable 17-1, p.
1063).The p16 (INK4) protein-whichis produced when cells are stressed-inhibits cell-cycle progression by preventing the formation of an active cyclin D-Cdk4 complex; it is an important component of the normal cell-cycle-arrest response to stress.Some glioblastomasand breast cancers have amplified the genes encoding Cdka or cyclin D, thusfavoring cell proliferation. And deletion or inactivation of the p16 gene is common in many forms of human cancer. In cancers in which mutations do notinactivate the pl6 gene, DNA methylation of its regulatory region often silencesthe gene; this is an example of an epigenetic change contributing to the development of cancer.
Mutation in any one component of a given pathway is sufficient to inactivate the pathway and promote cancer. As expected, therefore, aFigure20-37 Chartof the majorsignalingpathwaysrelevantto cancerinhuman cells,indicatingthe cellularlocationsof someof the Proteinsmodifiedby mutationin cancers.Productsof both oncogenesand tumorgenesoftenact withinthesuppressorIndividualsignalingsamepathways.proteinsare indicatedby redcircles,withcomponentsandthe cancer-criticalin thisdiscussedcontrolmechanismsandchapterin green.StimulatorYbetweenproteinsinhibitoryinteractionsasshownin the keY.aredesignated(Adaptedfrom D.HanahanandWithR.A.Weinberg,Cell100:57'70,2000.from Elsevier.)oermission1244Chapter20:Cancer(A)(B)IIcyclinD-Cdk4comprex(a Cdkinhibitor)(a G,-Cdk)NON-PROLIFERATINGC EL LPROLIFERATINGC EL Lp 1 6i n a c t i v eor absenta c t i v ep 15IJ-@IIdr*s*;q,#FIttranscriptionoftarget genesthatcontrol entry intoS phase( a n i n h i b i t o ro f ag e n er e g u l a t o r yprotein)/z7y11$IIt(a generegulatoryprotein)P\:active Rba,.
/P:lii n a c t i v eR b/o*;*'i]',%*;*;n-active E2Fexpressionof S-phaseg e n e si s i n h i b i t e d---jtL*expressionof S-phasegenesis activatedFigure20-38 The pathway by which Rb controls cell cycleentry containsboth proto-oncogenesand tumor suppressorgenes.All the componentsof this pathwayhavebeenfound to be alteredby mutationin humancancers(productsofproto-oncogenes,green;productsoftumor suppressorgenes,red;E2Fis shownin b/uebecauseit hasboth inhibitoryandstimulatoryactions,dependingon the other proteinsthat areboundto it).In mostcases,only one of the componentsisalteredin any individualtumor.(A)A simplifiedview of the dependencyrelationshipsin this pathway;seeFigurej7-62 forfurtherdetails.(B)The Rb proteininhibitsentry into the cell-divisioncyclewhen it is unphosphorylated.Theiomplex ofCdk4and cyclinD phosphorylatesRb,therebyencouragingp16 inhibitsthecellproliferation.Whena cellis stressed,formationof an activeCdk4-cyclinD complex,preventingproliferation.Inactivationof Rbor p16 by mutationencouragescelldivision(thuseachcan be regardedasa tumor suppressor),whileoveractivityof Cdk4or cyclinD encouragescelldivision(thuseachcan be regardedasa proto-oncogene).cancer rarely inactivates more than one component in a pathway: this wouldbring no additional benefit for the cancer'sevolution.DistinctPathwaysMayMediatethe Disregulationof cell-cycleProgressionand the Disregulationof cell Growthin cancercellsAs described in chapter lz, a special cell-cycle control system ensures thattumor-suppressor gene mutation, in many different cancers,is loss of the prENphosphatase,whose normal function is to limit Akt activation by dephosphorylating the molecules that PI 3-kinase phosphorylates.1245THEMOLECULARBASISOFCANCER_CELLBEHAVIORgrowth {actormrrogent3(\,,,.:.t1.,':rr''tlli:,lt:rt,l:iil.i:il:,:.il:.1':.',1'lr'rr.,,./tl/\'n-1...iPTENPl(4'5)P':iIPIPoPPCYTosoL-*PoP./\\activationactivationneededforneededtod r i v et h e n u t r i e n tu p t a k ec e l lc y c l e a n d u t i l i z a t i o nC?15kinase\tyrosine::dg..ePl 3-kinase\i+IC E L LG R O W T HA N D P R O L I F E R A T I O NIincreasedpyruvareractive ATPcitrate lyase(AcL)inffEasedProtqifisYflthesis-A'acetylCoA(A)excesscitrateexported tocytosol+++fatty acidscholesterolisoprenoids+(B)mitochondrionThe abnormal activation of the PI 3-kinase/Akt pathway, which normallyoccurs early in the process of tumor progression, explains the excessiverate ofglycolysis that is observed in tumor cells, knor,r,nas the Warburg effect.
Accompanied by excretion of excesspyruvate as lactate, the excessiveglucose uptakeby cancer cells is used to locate tumors by modern whole-body imaging techniques (seeFigure 20-l).ApoptosisAllowCancerCellsMutationsin GenesThatRegulateto SurviveWhenTheyShouldNotControl of cell numbers depends on maintaining a balance between cell proliferation and cell death. In the germinal centers of lymph nodes, for example, Bcells proliferate rapidly, but most of their progeny are eliminated by apoptosis.Correct regulation of apoptosis is thus essentialin maintaining the normal balance of cell birth and death in tissues that undergo cell turnover.
It also has avital role in eliminating damaged or stressedcells. As described in Chapter lB,animal cells commit suicide by undergoing apoptosis when they sense thatsomething has gone drastically wrong-when their DNA is severely damaged,for example, or when they are deprived of extracellular survival signals that tellthem they are in their proper place. As previously discussed (seeFigure 20-14),cancer cells are relatively resistant to apoptosis, which allows them to increasein number and survive where they should not.Mutations in apoptosis-control genesusually account for this resistance.Oneprotein that normally inhibits apoptosis,called Bcl2, was discoveredand namedbecause its expression is activated by a chromosomal translocation in a B-celllyrrphoma.
The translocation places the Bcl2 gene under the control of a regulatory DNA sequence that drives Bcl2 overexpression. This allows the survival of B.emtrana bi*sYntle$e,required'forcetfgrowth'Figure20-39 CellsmaYrequiretwotypes of signalsto proliferate.(A)ln orderto multiplysuccessfully,mostto requirenormalcellsaresuspectedsignalsthat drivecellboth extracellularcycleprogression(herered mitogen)andsignalsthat drivecellgrowthextracellular(hereb/uegrowth factor).(B)Diagramofthe signalingsystemcontainingAkt thatdrivescellgrowththroughgreatlystimulatingglucoseuPtakeandof theincludinga conversionutilization,excesscitric acid producedfrom sugarin mitochondriainto theintermediatesacetylCoAthat is neededin the cytosoland new membranefor lipidsynthesisproduction.As indicated,ProteinThissystemis alsoincreased.synthesisbecomesabnormallyactivatedearlyintumor progresslon.'1246Chapter20:CancerIirmphocltes that would normally have died, greatly increasing the number of Bcells and contributing to the development of the B-cell cancer.One of the genesinvolved in the control of apoptosis is mutated in an exceptionally wide range of cancers.
This tumor suppressor gene encodes a proteinthat stands at a crucial intersection in the network of intracellular control pathways governing a cell'sresponsesto DNA damage and various other cell stresses,including low oxygen (hypoxia) and growth factor deprivation. The protein istumor protein p53, and it is produced by the Tp53 gene,more commonly knora,rras p53. As we now explain, when p53 is defective, genetically damaged dividingcells do not merely fail to die; they persist in proliferating, accumulating yetmore genetic damage that can increase malignancy.Mutationsin the p53GeneAllowManyCancerCellsto Surviveand ProliferateDespiteDNADamageThe p53 gene-named for the molecular mass of its protein product-may bethe most important gene preventing human cancer. Either this tumor suppressor gene or other components in the p53 pathway are mutated in nearly allhuman cancers.\A/hyis p53 so critical? The answer lies in its multifaceted function in cell-cycle control, in apoptosis, and in maintenance of genetic stabilityall aspectsof the fundamental role of the p53 protein in protecting the organismagainst the consequencesof cell damage and the risk of cancer.In contrast to Rb, most body cells have very little p53 protein under normalconditions: although the protein is synthesized,it is rapidly degraded.Moreover,p53 is not essential for normal development.
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
