23.4 Flashcards
23.4 How mutations cause cancer
mutant allels that lead to cancer are refefred to as cancer egenes but this is a misnoemr bc all cancer genes are mutant alleles of normmal egnes
thyeve identfied more than 100 genes in whcih mutatiosn fuel progression of cancer
cancer genes can be subdivided into two classes
genes whose mutant alleles act in a dom fashion to proote cancer are protoconcogenes and the cancer causing mutant alleles are oncogenes
in a diploid cell one mutant oncogene alleles is enough to cause cancer phenotype
genes whose mutant allele acts in recessive manner to cause cancer are tumour supressor genes
in diploid cell, both copies of tumro supressor have to be mutant to make it abnormal
protooncegrens often encode proteins needed for cell cycle progression
they act like acelortor to make car go front
the onogenic muyation inc gene expression or enhances products efficiency so cell udnergoes more mitoic cell cycels
oncogenic mutation is like pressing harder on acelrtor
single oncoegnic mutation has dom gain of function efefct in making the cell divide more rfequntely
eahc normal copy of a tumor supressor gene encodes a protein that eitehr slows cell division down or gaurds against genome instability
so its like two redunatn brakes
the mutations in tehse genes can cause cancer are loss of function mutation like removing ur feet from the brake
if one is tehre teh brake still works but if u take both off it doesnt
mutations in the genes are recessive bc both must be inactated to cause efefct
when neitehr is functional then cell polifeates faster and/or accumalte mutatiosn at faster rate
most cocners requrie acucmaltin of multiple mutation in protooncegrnes and in tumrour supressor
these are drivers of cancer bc they initiation cycles of prolfertaion and muation that leads to maliganncy
finding oncogenes through asociation with tumoru viruses
tumor viruses are usful tools for idenftuing cancer causing genes bc the small and charcetrized viral genomes often associate with oncogens or protoonocgenes
mnay viruses that generate tumors in animals are retroviruses hwose RNA genomes upon infetcing cells are copied to cDNA which then intergates into the host chrosmome
by chance, the site onto which viral cDNA inetgrates is lcoated near protooncegrne in host cell genome
rare deletions can subequently bring the viral cDNA and protooncegne closer
later when teh cDNA is trancirbed form chromoe,s the viral RNAs that result can pick up copies of host protooncogene
RNA tumor viruses can contirbute to cancer in three ways:
- whne virsues carrying protonocgenes are propogated,gain of function mutations can occur in the protooconegen to oncevrt it into an oncogene - when a virus carrying oncogene infetcs new host cell, the ocngene is expresed and its protein product caues new host cell to polferate abornally
- protoonciegens or oncogenes incorpated into viral genomes are placed udner transcirptonal control of pwoerful promoters and enhancers on vrial chromsome - they are tarsncirebd at highr ate leaidng toe xcessive protein product
- whne virla cDNA integrates to protonocgene in host, teh same protomerts adn ehancers elevate trasncription of protooncgene reuslting in excessive amounts of protoncgene encoded protein
scitentsist usualy look for oncogenes carried by viral genomes or tehy lok at genomes of tumor induced by retroviruses for genes next to viral cDNA inetrgtaion sites
finding oncogenes through cell transormatin assays
diff stategy to idenfty otehr ocgnogenes
researcehrs isolate DNA form turmor cells and expose noncancerous cells in culture to tumor dna
if noncancerous cell picks up frga of tumor dna then some are trransofmred into cells capable of producing tumors
this effect occurs bc oncogene alleles are dom to normal protooconegne alleles in genome of noncaneous cell
they islate genomic dna from tumors, fragment the dna into gene sized pieces, and then add dna to noncanceorus mouse cells
some cells take up oncgene, lose contact inhibition and form transfomred foci in petri plates
cells from transformed foci often produce tumors hwne injected into mice
resreahcers then identfy the human oncgene repsonible for transofmrtaion of the mouse cells by finding the human dna in the transfomred foci
this can be done by looking for adjcent transorposable elemnts SINES known as Alu sequences that appear only in the human but not mouse genome
the oncogenes identfied in this way like thsoe dicsered in tumor viruses, are mutant allles of normal cellualr protooncegens that have mutated to abonrally active forms
how oncogenes contribute to cancer
the coresponding protooncgene performs a role in signnal trasnduction pathway eneded for normal cell polifertaion
many dfif types of mutagentci events can conevrt a normal protoncgene into cancer pormoting oncogene but all of these mutations have some kind of gain of function domnint effect
ras:
several oncogenic alleles of Ras gene ar epoint mutants encoding Ras proteins that are always - constivly- in the GTP actviated form
the plifertaive cell signalling pathwya is always ON in cell carrying a contsievly active Ras oncogene so the cell will divide whetehr or not a growth fatcor is present
c-Abl:
genomes of cancours cells in many ppl with lukeima contain translcoation b/w hcormosmes 9 and 22 that fuses gene named c-abl with gene caleld bcr
the fused gene is an oncogene that encodes a hydbrid protein
the c-Abl part of the protein is a protein trysine kinase which adds phosphate groups to trysimne aa in otehr proteisn
this partcpates in certain growth factor idncued signal transudction pathways
the Bcr/c-Able protein is always active even in absence of growth fatcors
Her2:
abt 20% breast cancer overexpres human epidemral growth fcors recpetor 2
the protein is memebr of growthrecpetor but is orphan recptors bc growth fatcor that actiavtes it isnt nkown
cells with too many copies of Her2 atcviate transduction patwhays ocntitvly and cause innapro divisions
in some Her2 pos cells, overexpresion of teh protein reflects tremendous amplfictaion of the numebr of copies of the Her 2 gene
additonal copies are found on double minute chromsomes
this sugegst that a mitici ancestor of cancer cell mustve been accumaltes mutations in egne encoding dna repair enzymes or compoents of dna damage checkpont
this would allow amp of certain genome regions and that wouldve incldued her 2 gene
Mutations in tumor supressor can relase cell cycle brake
some mutant tumor supresor genes are recessive alleles of genes whose normal alleles help put cell divison on hld
when both wildtype copies are lost, a retsraint or brake on polifertaion is released
otehr tumor surpoesor genes encode dna repair proteins
loss fo both normal alles inc muattion rate nad produce driver mutation in otehr cancer genes
finding tumor suppressor genes through analysis of pedigrees and genomes
theyve found many tumor supressor egens through genomic analysis of fmailies with inerted predispoitionto types of cnacer or through analysis of specific chromsoal regions that are deleted reproducbly in certain tumor types
retinoblastoma orpvdes exmaples of such an OD process
as cancers of colour perceiving cone cells in retina, retinobalstoma tumorus are easy to diagnose and remove before invasive
its an cancer that can be inehrted in dom fashion
karyote of norml noncancerous tissues form many ppl with retinoblasoma reveal heteroyfisty for deletions in long arm of chromsome 13
they carry one nromal and one deleted copy of 13q
cancerous retinal cells from some of these ppl are homoyzgous for same chrosmoem 12 deletions that are het in noncanours cells
deletions vary in size and positon but all remove band 13q14
this band includes gene whose rmeoval contirbutes to dvelopment of retinobalsoma; RB is the gene
het cells in normal tissue carry on copy of RB+ wildtype which preevtns cell from being cancerous
tumor cells homzygous for deltion dont carry any copies of RB+ and they diide out of contorl
they located general region carrying the gene by looking for DNA sequences in band 13q14 that were lost in all of the deltions associated with the ehrediatry condition
they tehn ID the specific gene by chatcetrizng small deletion that affected only one tarsncirptnal unit - RB gene itself
it endoed protein involved in rgeulating cell cycle
RB is tumro supresor gene: protein specifies help prevent cells form being ccanceorus
and caner happens when het for RB dletion loses remiaing copy
cacnceR: dom at orgnaimal level but recesive at cellular
hows it inerted in dom fashion if deletion of RB gene is recesisve to wildtype RB+
RB deltions are dom at leevl of orgnaims bc the strong likliehood that one of million cells het for dletion will udngro event to lose the remainng RB+ alelel resulting in muatnt cell
this cell then mutlipleis out of control
many rare events can knowck out remianng RB+ alelle in het cell
all tehse events prduce a loss of het bc they chainge an RB-/R+ into RB-/RB-
bc eyes exposed to UV the copy can be deleted for suffer inacttivating point muation
it can be lost by nondijsunction
mitotic reocmb or gene conevrsion could substite it with muation or deletion from homolog chrosmome inehrted froma fefcted parent
the hypptehsis that both alelels need to be gone are supported by retinlbastoma and that it happens late in life
ppl with spradic retinoblastoma have tumor in one eye but ppl with inerted have it in both
sporadic retinsbalsoam is rare bc they requrie two sucesisev idnepent hits in clone of cells
ppl with inetred rb- only requrie one to lose function
loss of both copies can intuate vicous feedback loop causin cancer
subsqeunct gentic chnages occur that create oncogenes or disurpt function of otehr tumor supresor genes, inc teh oncogenic protenal of cells in lcone
how tumor supresor muations contirbuet to cancer
normal copies of gene encode proteins that can have one or more of tehse functions:
- part of cell prolifertaion machinery that act in neg fahsion
- componets of cell cycle checkpoints
- involved in dna dmaage repair
- promote apoptosis when dna damage great
RB:
unphosphrylated wildtyep Rb protein delyas cell cycle progresion into S phase by inihibyon of E2F transcirption factor
in RB- and RB- cells that have no Rb function, E2F not inhibited so it progeses into S before ready or inabsnce of growth fatcor
p53:
essential for G1 to S checkpoint
the protein anc checkpoint is actiated in wildtupe by strrssufl conditions like single syranded breaks in DNA
actviation of p53 induces expresion of suites of egnes whose products block action of CDK -cyclin complexes, help rpeiar DNA damage or promote apoptosis when all else fails
in p53-/p53- none of thsoe vents occur
the dna damges cna contibue into S phase
single strand brekas become double when replcited leaidngto manyc hrosmome rearrnagements
cells with damage dont die by apoposis as tehy should
BRCA1 and BRCA2:
these breast cancer genes encode protein components of mahcienry for repaiding double strand breaks
females het for eitehr muation have higehr chance of dveloing breats or ovarian cnacer
if cell loses remianing normal copy, the muation rate inc eventually producing new dirver of miations which can lead to maliganncy
