Genes, myc

Myc

Myc (cMyc) is a gene that regulates other genes. It codes for a protein that binds to the DNA of other genes. When Myc is mutated, or overexpressed, the protein doesn't bind correctly, and often causes cancer.

When a gene like Myc is altered to cause cancer, the cancerous version of the gene is called an oncogene. The healthy version of the gene that it is derived from is called a protooncogene.

Myc gene encodes for a transcription factor that regulates expression of 15% of all genes through binding on Enhancer Box sequences (E-boxes) and recruiting histone acetyltransferases (HATs). Myc belongs to Myc family of transcription factors, which also includes N-Myc and L-Myc genes. Myc-family transcription factors contain the bHLH/LZ (basic Helix-Loop-Helix Leucine Zipper) domain.

A mutated version of Myc is found in many cancers which causes Myc to be persistently expressed. This leads to the unregulated expression of many genes some of which are involved in cell proliferation and results in the formation of cancer. A common translocation which involves Myc is t(8:14) is involved in the development of a lymphoma.

Discovery

Myc gene was first discovered in Burkitt's lymphoma patients. In Burkitt's lymphoma, cancer cells show chromosomal translocations, in which Chromosome 8 is frequently involved. Cloning the break point of the fusion chromosomes revealed a gene that was similar to myelocytomatosis viral oncogene (v-Myc). Thus, the newfound cellular gene was named c-Myc.

Structure

Myc belongs to Myc family of transcription factors, which also includes N-Myc and L-Myc genes. Myc family of transcription factors contain bHLH/LZ (basic Helix-Loop-Helix Leucine Zipper) domain. Myc protein, through its bHLH domain can bind to DNA, while the leucine zipper domain allows the dimerisation with its partner Max, another bHLH transcription factor.

Molecular Function

Myc protein is a transcription factor that activates expression of a great number of genes through binding on consensus sequences (Enhancer Box sequences (E-boxes)) and recruiting histone acetyltransferases (HATs). It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 co-activator, it inhibits expression of Miz-1 target genes.

Myc is activated upon various mitogenic signals such as Wnt, Shh and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects. The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (upregulates Bcl-2), differentiation and stem cell self-renewal. Myc is a very strong proto-oncogene and it is very often found to be upregulated in many types of cancers.

Animal Models

During the discovery of Myc gene, it was realized that chromosomes that translocate to Chromosome 8 contained immunoglobulin genes at the break point. Enhancers that normally drive expression of immunoglobin genes, now lead to overexpression of Myc proto-oncogene in lymphoma cells. To study the mechanism of tumorigenesis in Burkitt's lymphoma by mimicking expression pattern of Myc in these cancer cells, transgenic mouse models were developed. Myc gene placed under the control of IgM heavy chain enhancer in transgenic mice gives rise to mainly lymphomas. Later on, to study effects of Myc in other types of cancer, transgenic mice that overexpress Myc in different tissues (liver, breast) were also made. In all these mouse models overexpression of Myc causes tumorigenesis, illustrating the potency of Myc oncogene.

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