Myc


Myc is a family of regulator genes and proto-oncogenes that code for transcription factors. The Myc family consists of three related human genes: c-myc, l-myc, and n-myc. c-myc was the first gene to be discovered in this family, due to homology with the viral gene v-myc.
In cancer, c-myc is often constitutively expressed. This leads to the increased expression of many genes, some of which are involved in cell proliferation, contributing to the formation of cancer. A common human translocation involving c-myc is critical to the development of most cases of Burkitt lymphoma. Constitutive upregulation of Myc genes have also been observed in carcinoma of the cervix, colon, breast, lung and stomach. Myc is thus viewed as a promising target for anti-cancer drugs. Unfortunately, Myc possesses several features that render it undruggable such that any anti-cancer drugs for Myc dysregulation will require acting on the protein indirectly, i.e. targeting the mRNA for the protein rather than a small molecule that targets the protein itself.
In the human genome, C-myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on enhancer box sequences.
In addition to its role as a classical transcription factor, N-myc may recruit histone acetyltransferases. This allows it to regulate global chromatin structure via histone acetylation.

Discovery

The Myc family was first established after discovery of homology between an oncogene carried by the Avian virus, Myelocytomatosis and a human gene over-expressed in various cancers, cellular Myc. Later, discovery of further homologous genes in humans led to the addition of n-Myc and l-Myc to the family of genes.
The most frequently discussed example of c-Myc as a proto-oncogene is its implication in Burkitt's lymphoma. In Burkitt's lymphoma, cancer cells show chromosomal translocations, most commonly between chromosome 8 and chromosome 14 . This causes c-Myc to be placed downstream of the highly active immunoglobulin promoter region, leading to overexpression of Myc.

Structure

The protein product of Myc family genes all belong to the Myc family of transcription factors, which contain bHLH and LZ structural motifs. The bHLH motif allows Myc proteins to bind with DNA, while the leucine zipper TF-binding motif allows dimerization with Max, another bHLH transcription factor.
Myc mRNA contains an IRES that allows the RNA to be translated into protein when 5' cap-dependent translation is inhibited, such as during viral infection.

Function

Myc proteins are transcription factors that activate expression of many pro-proliferative genes through binding enhancer box sequences and recruiting histone acetyltransferases. Myc is thought to function by upregulating transcript elongation of actively transcribed genes through the recruitment of elongation factors. 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. In addition, myc has a direct role in the control of DNA replication. This activity could contribute to DNA amplification in cancer cells.
Myc is activated upon various mitogenic signals such as serum stimulation or by Wnt, Shh and EGF.
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, but it also plays a very important role in regulating cell growth, apoptosis, differentiation, and stem cell self-renewal. Nucleotide metabolism genes are upregulated by Myc, which are necessary for Myc induced proliferation or cell growth.
There have been several studies that have clearly indicated Myc's role in cell competition.
A major effect of c-myc is B cell proliferation, and gain of MYC has been associated with B cell malignancies and their increased aggressiveness, including histological transformation.
c-Myc induces MTDH gene expression and in turn itself requires AEG-1 oncogene for its expression.

Myc-nick

Myc-nick is a cytoplasmic form of Myc produced by a partial proteolytic cleavage of full-length c-Myc and N-Myc. Myc cleavage is mediated by the calpain family of calcium-dependent cytosolic proteases.
The cleavage of Myc by calpains is a constitutive process but is enhanced under conditions that require rapid downregulation of Myc levels, such as during terminal differentiation. Upon cleavage, the C-terminus of Myc is degraded, while Myc-nick, the N-terminal segment 298-residue segment remains in the cytoplasm. Myc-nick contains binding domains for histone acetyltransferases and for ubiquitin ligases.
The functions of Myc-nick are currently under investigation, but this new Myc family member was found to regulate cell morphology, at least in part, by interacting with acetyl transferases to promote the acetylation of α-tubulin. Ectopic expression of Myc-nick accelerates the differentiation of committed myoblasts into muscle cells.

Clinical significance

A large body of evidence shows that Myc genes and proteins are highly relevant for treating tumors. Except for early response genes, Myc universally upregulates gene expression. Furthermore, the upregulation is nonlinear. Genes for which expression is already significantly upregulated in the absence of Myc are strongly boosted in the presence of Myc, whereas genes for which expression is low in the absence Myc get only a small boost when Myc is present.
Inactivation of SUMO-activating enzyme in the presence of Myc hyperactivation results in mitotic catastrophe and cell death in cancer cells. Hence inhibitors of SUMOylation may be a possible treatment for cancer.
Amplification of the MYC gene was found in a significant number of epithelial ovarian cancer cases. In TCGA datasets, the amplification of Myc occurs in several cancer types, including breast, colorectal, pancreatic, gastric, and uterine cancers.
In the experimental transformation process of normal cells into cancer cells, the MYC gene can cooperate with the RAS gene.
Expression of Myc is highly dependent on BRD4 function in some cancers. BET inhibitors have been used to successfully block Myc function in pre-clinical cancer models and are currently being evaluated in clinical trials.

Animal models

In Drosophila Myc is encoded by the diminutive locus,. Classical diminutive alleles resulted in a viable animal with small body size. Drosophila has subsequently been used to implicate Myc in cell competition, endoreplication, and cell growth.
During the discovery of Myc gene, it was realized that chromosomes that reciprocally translocate to chromosome 8 contained immunoglobulin genes at the break-point. To study the mechanism of tumorigenesis in Burkitt 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, in order to study effects of Myc in other types of cancer, transgenic mice that overexpress Myc in different tissues were also made. In all these mouse models overexpression of Myc causes tumorigenesis, illustrating the potency of Myc oncogene.
In a study with mice, reduced expression of Myc was shown to induce longevity, with significantly extended median and maximum lifespans in both sexes and a reduced mortality rate across all ages, better health, cancer progression was slower, better metabolism and they had smaller bodies. Also, Less TOR, AKT, S6K and other changes in energy and metabolic pathways. The study by John M. Sedivy and others used Cre-Loxp -recombinase to knockout one copy of Myc and this resulted in a "Haplo-insufficient" genotype noted as Myc+/-. The phenotypes seen oppose the effects of normal aging and are shared with many other long-lived mouse models such as CR ames dwarf, rapamycin, metformin and resveratrol. One study found that Myc and p53 genes were key to the survival of chronic myeloid leukaemia cells. Targeting Myc and p53 proteins with drugs gave positive results on mice with CML.

Relationship to stem cells

c-Myc plays a major role in the generation of induced pluripotent stem cells. It is one of the original factors discovered by Yamanaka et al. to encourage cells to return to a 'stem-like' state alongside transcription factors Oct4, Sox2 and Klf4. It has since been shown that it is possible to generate iPSCs without c-Myc.

Interactions

Myc has been shown to interact with:
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