Activation of proto-oncogenes by insertions, translocations and amplification

Three different kinds of known insertions of retroviral genome in c-myc gene, leading to activation of c-myc gene
Fig. 45.4. Three different kinds of known insertions of retroviral genome in c-myc gene, leading to activation of c-myc gene.
There are examples available, when events like insertions, translocations or amplification of DNA sequences of proto-oncogenes lead to their activation, although the nucleotide sequence remains unaltered. These mechanisms have been studied in c-myc, whose expression is elevated by these events leading to tumour formation.

Insertions of retroviral sequences
The c-myc gene has three exons (El, E2, E3), El representing the first untranslated (but transcribed) leader sequence, and the remaining two coding for c-myc protein.
Following three classes of insertions in c-myc gene are known (Fig. 45.4). (i) The retroviral genome may be inserted in the first intron, so that its LTR (long terminal repeat) works as an efficient promoter increasing the level of expression of c-myc protein coded by El and E2. The transcript also lacks the untranslated leader sequence, (ii) The retroviral genome is inserted in reverse orientation in the first intron or upstream to this intron and its LTR works as an enhancer, (iii) The retroviral genome may also be inserted downstream of c-myc gene, and LTR may work as aa enhancer.
Three different kinds of known insertions of retroviral genome in c-myc gene, leading to activation of c-myc gene
Fig. 45.4. Three different kinds of known insertions of retroviral genome in c-myc gene, leading to activation of c-myc gene.

There are also other oncogenes, which are activated to make tumours by the insertion of retroviral genome. Following are some examples : c-erbB, c-myb, c-mos, c-H-ras and c-raf, int 1, int 2.

Translocations leading to activation of c-myc gene; in B cells c-myc is translocated to the proximity of Ig locus, while in T cells, it is translocated to the vicinity of TcRα locus
Fig. 45.5. Translocations leading to activation of c-myc gene; in B cells c-myc is translocated to the proximity of Ig locus, while in T cells, it is translocated to the vicinity of TcRα locus (in both cases c-myc gets activated).

A translocation between chromosome 22 and chromosome 9 generating a Philadelphia chromosome (PH1), associated with chronic myelogenous leukemia (CML)
Fig. 45.6. A translocation between chromosome 22 and chromosome 9 generating a Philadelphia chromosome (PH1), associated with chronic myelogenous leukemia (CML).
Chromosomal translocations leading to activation of proto-oncogenes
In some cancerous cells; chromosomal translocations have been discovered, where an oncogene of one chromosome is brought into the proximity of an Ig locus on another chromosome (e.g. plasmacytomas in the mouse and Burkitt lymphomas in man). Such translocations lead to activation of a proto-oncogene like c-myc (Fig. 45.5), which is located on chromosome 8 in humans and on chromosome 15 in mouse. Due to translocation, the c-myc is brought in close proximity of Ig gene on chromosome 14 in humans and chromosome 12 in mouse.

Another case, where a translocation activates an oncogene involves Philadelphia (PH1) chromosome found in chronic myelogenoup leukemia (CML). This translocation involves transfer of a 5000kb region from the end of chromosome 9 carrying c-abl to the bcr locus (breakpoint cluster region = 5.8kb) of chromosome 22 (Fig. 45.6). This translocation gives a bcr-abl fusion protein of 210,000 daltons (70,000 belonging to bcr and ~ 140,000 is c-Abl protein). Perhaps the fusion, or loss of N-terminal sequence, changes the conformation of c-Abl protein and activates a latent oncogenic potential.

Translocations leading to activation of c-myc gene; in B cells c-myc is translocated to the proximity of Ig locus, while in T cells, it is translocated to the vicinity of TcRα locus
Fig. 45.5. Translocations leading to activation of c-myc gene; in B cells c-myc is translocated to the proximity of Ig locus, while in T cells, it is translocated to the vicinity of TcRα locus (in both cases c-myc gets activated).

A translocation between chromosome 22 and chromosome 9 generating a Philadelphia chromosome (PH1), associated with chronic myelogenous leukemia (CML)
Fig. 45.6. A translocation between chromosome 22 and chromosome 9 generating a Philadelphia chromosome (PH1), associated with chronic myelogenous leukemia (CML).

Amplification of oncogenes in some tumours
Many tumor cell lines have visible regions of chromosomal amplification containing a known oncogene. In other cases a particular oncogene is amplified, as revealed by molecular probes, although the amplification is not visible from chromosome morphology. This amplification leads to over-expression of the gene leading to tumour formation. In amplified DNA only, two new cellular genes, N-myc and L-myc were discovered, which had partial homology with c-myc.

Transgenic mice for a study ofoncogenic potential of c-myc gene
A normal c-myc gene linked to either an Ig-H enhancer or to an LTR (enhancer) derived from MMTV, when used for the production of transgenic mice, the latter developed a variety of cancers. In these cases, over-expression of c-myc gene is responsible for the development of cancers.

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