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Carcinogenesis: Mechanisms and Models Chapter | 20 349

VetBooks.ir Activation of Oncogenes and Inactivation nonreceptor tyrosine kinases, G-protein-coupled receptors,
of Tumor Suppressor Genes are Intimately
membrane-associated G-proteins, serine-threnine kinases,
Associated With Tumor Development
transcription factors, and regulators of programmed cell
Proto-oncogenes may be activated by mutation, chromo- death. For example, Sis, Int-2 encode growth factors; Src,
somal rearrangement (e.g., translocations and inversions), Abl, erbB encode protein tyrosine kinases; Ras is a GTP-
or gene amplification to become a cellular oncogene (c- binding GTPase; and Fos, Jun, Myc, and Myb encode
onc). An example of cellular oncogenic activation through transcription factors. There are many other such exam-
gene amplification is Myc, which codes for a transcription ples. These proteins, when encoded by oncogenes, are
factor that plays a role in cell division. Generation of high called oncoproteins, which are either mutated or with
amounts of Myc oncogene product can also be due to unregulated expressions. In most cases, the oncogenes
high levels of transcription without gene amplification. encode mutant forms of the proteins so that they are not
This has been reported in Burkitt’s lymphoma where subject to the on-off regulation in response to mitogenic
translocation of the Myc proto-oncogene from its normal signals. In other words, the mitogenic signal is perpetually
location in chromosome 8 to chromosome 14 brings it “on,” resulting in uncontrolled cell proliferation.
close to the immunoglobulin heavy chain gene promoter. The cell growth and division suppressor effects are
As a result, c-Myc now finds itself in a region of vigorous also lost in the mutant p53 gene; p53 is a tumor suppres-
transcriptional activity, with a consequent overproduction sor gene that encodes a transcription factor (p53 protein).
of its product. The amino acids that are involved in DNA binding show
Another example of chromosomal translocation and the highest mutation rate in various cancers. This demon-
cellular oncogenic activation is found in chronic myeloge- strates how mutations in tumor suppressor genes can
nous leukemia (CML). In CML, a reciprocal translocation abrogate their tumor suppressor function by disrupting the
occurs between chromosomes 9 and 22 [t(9;22)]. A por- transcriptional regulation of their target genes. Another
tion on the long arm of chromosome 9 (9q) containing the role of p53 is to regulate apoptosis or programmed cell
Abl gene is translocated next to the Bcr gene on the long death by upregulating the proapoptotic gene Bax. Mutant
arm of chromosome 22 (22q). The altered chromosome 22 p53 cannot mediate apoptosis; thus cells with unrepaired
is called the Philadelphia chromosome (Ph ). The Bcr-Abl DNA damage are prevented from undergoing apoptosis.
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fusion gene produces higher levels of a fusion protein Bcr- Survival of these cells and their subsequent division may
Abl. The Abl portion of the fusion protein has constitutive lead to the development of tumor.
protein tyrosine kinase activity, whereas the Bcr portion of
the fusion protein can bind to many proteins. Binding of Viral Carcinogenesis
the Bcr-Abl fusion proteins with proteins involved in the
mitogenic signaling pathway can cause activation of mito- Viruses are implicated in approximately 15% of all can-
genic signaling and increased cell proliferation. cers, such as nasopharyngeal carcinoma, T-cell leukemias,
Tumor suppressor genes, which also participate in the hepatocellular carcinoma, and Kaposi’s sarcoma. Only a
regulation of normal cell growth, are usually inactivated small proportion of people infected with any of the human
by point mutations or truncation of their protein sequence tumor viruses develop tumors, and those that are infected
coupled with the loss of the normal allele. The first muta- rarely (if ever) serve as sources for ongoing transmission.
tion may be inherited or somatic. The second mutation Instead, most human tumor virus transmissions are
will often be a gross event leading to loss of heterozygos- asymptomatic or mildly symptomatic but do not lead to
ity and tumor suppressor function. This mechanism neoplasia (Butel, 2000; Moore and Chang, 2010).
provides support to the two-hit hypothesis of Alfred Oncogenes are found in both cancer-causing DNA viruses
Knudson, discussed earlier in the chapter. Frequent loss and RNA viruses. DNA viruses with oncogenic potential
of heterozygosity in the tumor cells provides support to are from six distinct viral families: hepatitis B viruses,
Knudson’s hypothesis. simian virus 40 (SV40) and polyomavirus, papilloma-
viruses, adenoviruses, herpesviruses, and poxviruses. In
contrast, members of only one family of RNA viruses, the
Oncogenes and Tumor Suppressor Genes Encode retroviruses, are capable of inducing oncogenic potential
Protein Products That Are Involved in the Regulation (Cooper, 1995). Papillomavirus, hepatitis B virus and
of Growth and Survival of Cells as Well as Kaposi’s sarcoma-associated herpes virus are the main
Programmed Cell Death DNA tumor viruses relevant in human cancer develop-
Proto-oncogenes encode proteins that are involved in the ment. Like the tumorigenic DNA viruses, there are tumor-
regulation of cell growth as well as division and differen- igenic retroviruses. Whereas DNA tumor viruses encode
tiation, such as growth factors, growth factor receptor- oncogenes of viral origin that are essential for viral repli-
associated tyrosine kinases, membrane-associated cation and cell transformation, transforming retroviruses