which integrate randomly into the host chromosomal DNA,include several genes that are expressed early in the course of viral replication.SV40 encodes two early proteins called largeT and little T,and polyoma encodes three early proteins calledlarge T,middle T,and little T.Each ofthese proteins plays arole in the malignant transformation ofvirus-infected cells.Most RNA viruses replicate in the cytosol and do notinduce malignant transformation.The exceptions are retro-viruses,which transcribe their RNA into DNA by means ofareverse-transcriptase enzyme and then integrate the tran-script into the host’s DNA.This process is similar in the cyto-pathic retroviruses such as HIV-1 and HIV-2 and in thetransforming retroviruses,which induce changes in the hostcell that lead to malignant transformation.In some cases,retrovirus-induced transformation is related to the presenceof
oncogenes,
or “cancer genes,”carried by the retrovirus.One ofthe best-studied transforming retroviruses is the
Rous sarcoma virus.
This virus carries an oncogene calledv-
src,
which encodes a 60-kDa protein kinase (v-Src) that cat-alyzes the addition ofphosphate to tyrosine residues on pro-teins.The first evidence that oncogenes alone could inducemalignant transformation came from studies ofthe v-
src
on-cogene from Rous sarcoma virus.When this oncogene wascloned and transfected into normal cells in culture,the cellsunderwent malignant transformation.
Oncogenes and Cancer Induction
In 1971,Howard Temin suggested that oncogenes might notbe unique to transforming viruses but might also be found innormal cells;indeed,he proposed that a virus might acquireoncogenes from the genome ofan infected cell.He calledthese cellular genes
proto-oncogenes,
or
cellular oncogenes
(c-
onc
),to distinguish them from their viral counterparts(v-
onc
).In the mid-1970s,J.M.Bishop and H.E.Varmusidentified a DNA sequence in normal chicken cells that ishomologous to v-
src
from Rous sarcoma virus.This cellularoncogene was designated c-
src.
Since these early discoveries,numerous cellular oncogenes have been identified.Sequence comparisons ofviral and cellular oncogenesreveal that they are highly conserved in evolution.Althoughmost cellular oncogenes consist ofa series ofexons and in-trons,their viral counterparts consist ofuninterrupted cod-ing sequences,suggesting that the virus might have acquiredthe oncogene through an intermediate RNA transcript fromwhich the intron sequences had been removed during RNAprocessing.The actual coding sequences ofviral oncogenesand the corresponding proto-oncogenes exhibit a high de-gree ofhomology;in some cases,a single point mutation isall that distinguishes a viral oncogene from the correspond-ing proto-oncogene.It has now become apparent that most,ifnot all,oncogenes (both viral and cellular) are derived fromcellular genes that encode various growth-controlling pro-teins.In addition,the proteins encoded by a particular onco-gene and its corresponding proto-oncogene appear to havevery similar functions.As described below,the conversion of a proto-oncogene into an oncogene appears in many cases toaccompany a change in the level ofexpression ofa normalgrowth-controlling protein.
Cancer-Associated Genes HaveMany Functions
Homeostasis in normal tissue is maintained by a highly reg-ulated process ofcellular proliferation balanced by cell death.Ifthere is an imbalance,either at the stage ofcellular prolif-eration or at the stage ofcell death,then a cancerous state willdevelop.Oncogenes and tumor suppressor genes have beenshown to play an important role in this process,by regulatingeither cellular proliferation or cell death.Cancer-associatedgenes can be divided into three categories that reflect thesedifferent activities,summarized in Table 22-1.
INDUCTION OF CELLULAR PROLIFERATION
One category ofproto-oncogenes and their oncogenic coun-terparts encodes proteins that induce cellular proliferation.Some ofthese proteins function as growth factors or growth-factor receptors.Included among these are
sis,
which encodesa form ofplatelet-derived growth factor,and
fms,erbB,
and
neu,
which encode growth-factor receptors.In normal cells,the expression ofgrowth factors and their receptors is care-fully regulated.Usually,one population ofcells secretes agrowth factor that acts on another population ofcells thatcarries the receptor for the factor,thus stimulating prolifera-tion ofthe second population.Inappropriate expression of either a growth factor or its receptor can result in uncon-trolled proliferation.Other oncogenes in this category encode products thatfunction in signal-transduction pathways or as transcriptionfactors.The
src
and
abl
oncogenes encode tyrosine kinases,and the
ras
oncogene encodes a GTP-binding protein.Theproducts ofthese genes act as signal transducers.The
myc, jun,
and
fos
oncogenes encode transcription factors.Overac-tivity ofany ofthese oncogenes may result in unregulatedproliferation.
INHIBITION OF CELLULAR PROLIFERATION
A second category ofcancer-associated genes—called
tumor-suppressor genes,
or anti-oncogenes—encodes proteins thatinhibit excessive cell proliferation.Inactivation ofthese re-sults in unregulated proliferation.The prototype ofthis cate-gory ofoncogenes is
Rb,
the retinoblastoma gene.Hereditaryretinoblastoma is a rare childhood cancer,in which tumorsdevelop from neural precursor cells in the immature retina.The affected child has inherited a mutated
Rb
allele;somaticinactivation ofthe remaining
Rb
allele leads to tumor growth.Probably the single most frequent genetic abnormality inhuman cancer is mutation in
p53,
which encodes a nuclearphosphoprotein.Over 90% ofsmall-cell lung cancers and
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