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Origin of viral Oncogenes

Regardless of how oncogenes induce cancers, it how seems

clear that retroviral oncogenes have evolved from normal cellular

protooncogenes. originally, it was thought that the cellular homologs of viral oncogenes might be relics of integrated retroviral proviruses.

However, this is clearly not the case. Comparisons of the nucleotide

sequences of viral oncogenes and the homologous cellular

protooncogenes have shown that these genes share major regions of

the sequence identity. The ey di!erence is that the celluar

protooncogenes contain intron, whereas viral oncogenes are single

e"ons. This is not consistent with the idea that cellular protooncogenes

have evolved from v#oncogenes on integrated proviruses. $nstead, it

strongly suggest that v#oncogenes are derived from ancestral cellular

protooncogenes. This di!erence is to be e"pected if the v#oncogenesevolved from cellular protooncogenes the retroviral genomes are R%&

and the intron sequences of R%& transcripts of protooncogenes should

be splice out during R%& processing. &ll the needs to occur is for an

mR%& copy of a protooncogene to be ligated into the R%& genome of a

retrovirus by a recombination mechanism that preserves the 'TR

regions of the viral genome. The viral reverse transcriptase will then

convert the mR%&#viral R%& hybrid into homologous (%& for

intregation into the host genome.

$n some case, di!erent retroviruses that infect distantly related

species have acquired copies of the same cellular protooncogene. $n

other case, closely related viruses contain oncogenes derived from

completely unrelated cellular protooncogenes.

)y comparing the nucleotide sequences of the v#oncogenes and

the homologous c#protooncogenes, the sites of the of breaage and

 joining in the recombination events that gave rise to the v#oncogenes

can sometimes be identi*ed. $n other cases, e"tensive rearrangements

have occurred, maing it impossible to identify the sites or

recombination involved in the acquisition of the oncogenes by the

retrovirus. $n several cases, the viral oncogenes encode fusion proteinscontaining part of the gag protein and the oncogenes product. $n most

cases, the retroviral acquisition of an oncogene has been accompanied

by the loss of viral genetic material required for replication. +uch

defective viruses can integrate normally as proviruses, but can only

produce progeny viruses in the presence of a helper virus- that

provides the missing function .

C&%CR &+ TH %( /RO(0CT O1 & 20'T$+T/ /ROC++

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1inally, we should emphasi3e that a large amount of data

indicates that the cancerous state is the end product of a multistep

process. The cell lines used in transfection e"periment are probably

already at some intermediate stage in the pathway, possibly simply

due to the selection for the ability to grow under cell calture conditions. The oncogenes#induced transformation observed in cell cultures is

undoubtedly only one part of a more comple" pathway.

$n fact, there is considerable evidence indicating that certain

oncogenes may have cooperative e!ect in promoting neoplastic

transformation. 2oreover, di!erent oncogenes seem to play di!erent

roles in oncogenic pathways in di!erent cell types. 1inally, seems liely

that di!erent molecular events are involved in the acquisition of the

enhanced proliferative capacity of cells, in the ability of tumors to

invade adjacent tissues, and in the capacity for metastasis. To whate"tent and in what roles protooncogenes and oncogenes are involve in

these processes in human cancers remain to be determined.

Regardless of the e"tent of their involvement in the formation of

malignant tumors, the ongoing and future investigation of

protooncogenes and oncogenes promise to yield important information

about the molecular circuitry that controls cell proliferation in higher

eucaryotes such as humans.