|V-myc myelocytomatosis viral oncogene homolog (avian)|
Structure of the c-Myc (red) in complex with Max (blue) and DNA (PDB 1nkp). Both proteins are binding the major groove of the DNA by forming a fork-like structure.
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Myc (c-Myc) is a regulator gene that codes for a transcription factor.
A mutated version of Myc is found in many cancers, which causes Myc to be constitutively (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 human translocation involving Myc is t(8;14) which is critical to the development of most cases of Burkitt's Lymphoma. A recent study demonstrated that temporary inhibition of Myc selectively kills mouse lung cancer cells, making it a potential cancer drug target.
It has been associated with carcinoma of the cervix, colon, breast, lung and stomach.
In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences (E-boxes) and recruiting histone acetyltransferases (HATs). This means that in addition to its role as a classical transcription factor, Myc also functions to regulate global chromatin structure by regulating histone acetylation both in gene-rich regions and at sites far from any known gene.
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.
Myc protein 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 dimerization with its partner Max, another bHLH transcription factor.
Myc mRNA contains an IRES (internal ribosome entry site) that allows the RNA to be translated into protein when 5' cap-dependent translation is inhibited, such as during viral infection.
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. In addition, myc has a direct role in the control of DNA replication.
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 (downregulates 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. Myc overexpression stimulates gene amplification, presumably through DNA over-replication.
Myc-nick is a cytoplasmic form of Myc produced by a partial proteolytic cleavage of full-length c-Myc and N-Myc. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923036/pdf/nihms219804.pdf). Myc cleavage is mediated by the calpain family of calcium-dependent cytosolic proteases (http://en.wikipedia.org/wiki/Calpain).
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 (containing the DNA binding domain) 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.
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, in order 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.
Myc has been shown to interact with NMI, NFYC, NFYB, Cyclin T1, RuvB-like 1, GTF2I, BRCA1, T-cell lymphoma invasion and metastasis-inducing protein 1, ACTL6A, PCAF, MYCBP2, MAPK8, Bcl-2, Transcription initiation protein SPT3 homolog, SAP130, DNMT3A, Mothers against decapentaplegic homolog 3, MAX, Mothers against decapentaplegic homolog 2, MYCBP, HTATIP, ZBTB17, Transformation/transcription domain-associated protein, TADA2L, PFDN5, MAPK1, TFAP2A, P73, TAF9, YY1, SMARCB1, SMARCA4, MLH1, EP400 and let-7.
A major effect of Myc is B cell proliferation.
c-Myc induces AEG-1 or MTDH gene expression and in turn itself requires AEG-1 oncogene for its expression.
It is associated with carcinoma of the cervix,colon,breast,lung and stomach.
In an online article posted on Thursday, December 8, 2011, from FOCUS, a Harvard University website offering news on important health-related discoveries made there, it was stated that,: "Researchers have found a way to kill human cells hijacked by a genetic accelerator that puts cancer cells into overdrive: the Myc oncogene. The discovery reveals new drug targets for Myc-driven cancers, which tend to be particularly aggressive. The results are to be published online December 8 in Science. In its non-cancerous, healthy form, Myc oversees how genetic information is translated into proteins, typically those involved in growing new cells. But mutations can cause Myc to become hyper-activated, or oncogenic, and when that happens, cells divide uncontrollably and form tumors. Myc-dependent cancer cells are addicted to the oncogene, to the extent that they’ll die if it’s disabled. Scientists have long tried to exploit this vulnerability in drug development. However, in its protein form, Myc is a notoriously difficult target, mainly because it lacks efficient binding sites for drug compounds. So Stephen Elledge, a professor in the Department of Genetics at Harvard Medical School, and a senior author on the paper, and his collaborator and co-senior author Thomas Westbrook, an assistant professor at the Baylor College of Medicine, opted for a different approach. They aimed to suppress Myc by disabling its helper genes rather than the oncogene itself. Taking advantage of “synthetic lethality,” or the cell-killing effect of having two incompatible mutations in a shared pathway, they hoped to mimic the success seen in studies of genes associated with inherited breast cancer. To find the genes, Elledge and Westbrook used a method that relies on tiny RNA molecules (dubbed short-hairpin RNA or shRNAs) that block the activity of specified genes. The scientists used those shRNAs in experiments with human breast epithelial cells in which Myc could be selectively hyper-activated. Each cell in the experiment contained just one silenced gene. If the cell died when Myc’s cancer activity was triggered, then that silenced gene was clearly one Myc needed to form tumors. Altogether they tested nearly 75,000 shRNAs, and ultimately found 403 potential candidates; some familiar to the field of Myc biology and some not. “These genes aren’t oncogenes in and of themselves, but they do code for proteins that Myc relies on to cause cancer,” said Elledge, who is also a professor of medicine at Brigham and Women’s Hospital. “We see them as potential targets for drug therapy—even if you can’t target Myc, you can target these other genes and inactivate its effects. ..."
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