ONCOGENES

Oncogenes are genes that induce cancer in animals. Their normal cellular counterparts are called ‘proto-oncogenes’. Mutations in two broad classes of genes namely proto-oncogenes and tumour-suppressor genes play a significant role in the development of cancer. The oncogenes produced by the mutations of proto-oncogenes encode oncoproteins that mediate the pathogenesis. In certain cases, the oncogenes produce the normal proteins; however, at higher than normal levels, mediate the development of cancer.

Cancer-causing viruses contain oncogenes or activate proto-oncogenes. For example, the Rous sarcoma virus (RSV), a transducing retrovirus, contains a gene called v-src gene that is very closely related to the proto-oncogene c-src. RSV and other oncogene-carrying viruses are believed to have arisen by incorporating or tranducing a normal cellular proto-oncogene into their genome. Subsequent mutation in the transduced gene converted them into a dominantly acting oncogene, which can bring about cell transformation in the presence of normal c-src proto-oncogene.

Mutations that result in the loss of function of tumour-suppressor genes are also considered oncogenic. These tumour-suppressor genes generally encode proteins that inhibit cellular proliferation. Five broad classes of proteins are generally recognized as being encoded by tumour-suppressor genes; they include:

 

Table 8.2 Some genes implicated in human cancers

Gene	Product	Cancer
Oncogenes
Genes encoding growth factors or their receptors
erb-B	Receptor for epidermal growth factor.	Glioblastoma (a brain cancer), breast cancer.
erb-B2	A growth factor receptor (gene also called neu).	Breast cancer, ovarian cancer, salivary gland cancer.
PDGF	Platelet-derived growth factor.	Glioma (a brain cancer).
RET	A growth factor receptor.	Thyroid cancer.
Genes encoding cytoplasmic relays in intracellular signalling pathways
K-ras	Protein kinase.	Lung cancer, colon cancer, ovarian cancer, pancreatic cancer.
N-ras	Protein kinase.	Leukaemias.
Genes encoding transcription factors that activate transcription of growth-promoting genes
c-myc	Transcription factor.	Lung cancer, breast cancer, stomach cancer leukaemias.
L-myc	Transcription factor.	Lung cancer.
N-myc	Transcription factor.	Neuroblastoma (a nerve cell cancer).
Genes encoding other kinds of proteins
bcl-2	Protein that blocks cell suicide.	Follicular B-cell lymphoma.
bcl-1	Cyclin D1, which stimulates the cell cycle clock (gene also called PRAD1).	Breast cancer, head and neck cancers.
MDM2	Protein antagonist of p53 tumour-suppressor protein.	A wide variety of sarcomas (connective tissue cancers).
Tumour-suppressor genes	Genes encoding cytoplasmic proteins
APC	Step in a signalling pathway.	Colon cancer, stomach cancer.
DPC4	A relay in signalling pathway that inhibits cell division.	Pancreatic cancer.
NF-1	Inhibitor of ras, a protein that stimulates cell division.	Neurofibroma, myeloid leukaemia.
NF-2	Inhibitor of ras.	Meningioma (brain cancer), schwannoma (cancer of cells supporting peripheral nerves).
Genes encoding nuclear proteins
MTS1	p16 protein, which slows the cell cycle clock.	A wide range of cancers.
p53	p53 protein, which halts cell division at the G1 checkpoint.	A wide range of cancers.
Rb	Rb protein, which acts as a master brake of the cell cycle.	Retinoblastoma, breast cancer, bone cancer, bladder cancer.
Genes encoding proteins of unknown cellular locations
BRCA1	?	Breast cancer, ovarian cancer.
BRCA2	?	Breast cancer.
VHL	?	Renal cell cancer.

 

1. Intracellular proteins that regulate cell cycle.
2. Receptors or signal transducers or developmental signals that inhibit cellular proliferation.
3. Checkpoint control proteins that arrest cell cycle if DNA is damaged or chromosomes are abnormal.
4. Proteins that induce apoptosis (programmed cell death).
5. Enzymes that participate in DNA repair.

Thus, the mutations of tumour-suppressor genes result in the loss of vital cellular regulatory functions and manifest in cancer (Figure 8.21).

The dual nature of oncogenes

 

During the normal development, the secreted signals such as Wnt and TGF β are frequently used to direct cells to particular developmental fates such as mitosis. The effects of such signals must be regulated. Mutations that prevent such mechanisms from operating are likely to be oncogenic.

Oncogenic receptors can promote cellular proliferation even in the absence of external growth factors. Oncogenes that encode cell surface receptors that transduce growth-promoting signals have been associated with several types of cancer. Some oncogenes even encode constitutively active signal transducing proteins; for example, ras^D genes. A point mutation that substitutes any amino acid for glycine at position 12 in the Ras sequence converts the normal protein into a constitutively active oncoprotein.

Proteins encoded by oncogenes cause changes in gene expression. For example, the c-jun and c-fos proto-oncogenes encode proteins that associate to form transcription factor called AP1, which binds to a sequence found in promoters and enhancers of many genes. Both can independently act as transcription factors. They function as oncoproteins by activating transcription of key enzymes that encode growth-promoting proteins or by inhibiting transcription of growth-repressing genes.

Normal growth and development depend on the balance between growth-promoting and growth-inhibiting pathways. Mutations that disrupt this balance can lead to cancer. Once a cell progress taken place in a point in late G₁ phase of the cell cycle called the restriction point, it becomes irreversibly committed to enter the S phase. D-type cyclins, cyclin-dependent kinases and Rb protein are all elements that control the passage through the restriction point. Mutations that cause the elevated levels of cyclin D1 are found in many cancers. Thus, mutations that promote unregulated passage from G₁ to S phases are oncogenic. The failure of cell cycle checkpoints can also lead to aneuploidy in tumour cells (Figure 8.21).

 

Figure 8.21 Oncogenes and tumourogenesis

 

Chromosomal abnormalities can lead to the activation of proto-oncogenes. A chromosomal trans-location that moves a strong enhancer near a proto-oncogene can lead to either over expression or to expression in a tissue where the proto-oncogene normally is not expressed; for example, the Philadelphia chromosome and chronic myelogenous leukaemia. The translocation of a portion of the chromosome creates a chimeric gene that includes the proto-oncogene c-ABL, causing c-ABL to be expressed and producing leukaemia.