Myc

V-myc avian myelocytomatosis viral oncogene homolog
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.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1A93, 1EE4, 1MV0, 1NKP, 2A93, 2OR9
Identifiers
Symbols	MYC ; MRTL; MYCC; bHLHe39; c-Myc
External IDs	OMIM: 190080 MGI: 97250 HomoloGene: 31092 ChEMBL: 1250348 GeneCards: MYC Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription • DNA binding • sequence-specific DNA binding transcription factor activity • protein binding • transcription factor binding • protein complex binding • protein dimerization activity • repressing transcription factor binding • E-box binding Cellular component • nucleus • nucleoplasm • nucleolus • cytosol • protein complex Biological process • negative regulation of transcription from RNA polymerase II promoter • MAPK cascade • branching involved in ureteric bud morphogenesis • positive regulation of mesenchymal cell proliferation • energy reserve metabolic process • chromatin remodeling • transcription, DNA-templated • transcription initiation from RNA polymerase II promoter • cellular iron ion homeostasis • cellular response to DNA damage stimulus • cell cycle arrest • transforming growth factor beta receptor signaling pathway • Notch signaling pathway • positive regulation of cell proliferation • response to gamma radiation • gene expression • regulation of gene expression • oxygen transport • regulation of telomere maintenance • negative regulation of stress-activated MAPK cascade • cellular response to UV • cellular response to drug • response to drug • negative regulation of apoptotic process • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • fibroblast apoptotic process • negative regulation of monocyte differentiation • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • positive regulation of fibroblast proliferation • negative regulation of fibroblast proliferation • positive regulation of epithelial cell proliferation • chromosome organization • negative regulation of cell division • canonical Wnt signaling pathway • response to growth factor • positive regulation of metanephric cap mesenchymal cell proliferation • positive regulation of DNA biosynthetic process • positive regulation of response to DNA damage stimulus Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4609	17869
Ensembl	ENSG00000136997	ENSMUSG00000022346
UniProt	P01106	P01108
RefSeq (mRNA)	NM_002467	NM_001177352
RefSeq (protein)	NP_002458	NP_001170823
Location (UCSC)	Chr 8: 127.74 – 127.74 Mb	Chr 15: 61.99 – 61.99 Mb
PubMed search	[1]	[2]

Myc (c-Myc) is a regulator gene that codes for a transcription factor. The protein encoded by this gene is a multifunctional, nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis and cellular transformation.

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 critical to the development of most cases of Burkitt Lymphoma. Malfunctions in Myc have also been found in carcinoma of the cervix, colon, breast, lung and stomach. Myc is thus viewed as a promising target for anti-cancer drugs.

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.

Discovery

Myc gene was first discovered in Burkitt lymphoma patients. In Burkitt 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 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 structural motif 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.

Function

Myc protein is a transcription factor that activates expression of many genes through binding 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.

There have been several studies that have clearly indicated Myc's role in cell competition.

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.

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 (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.

File:Myc-Nick.pdf

Clinical significance

Except for early response genes, Myc universally upregulates gene expression. Furthermore the upregulation is nonlinear. Genes whose expression is already significantly upregulated in the absence of Myc are strongly boosted in the presence of Myc, whereas genes whose expression is low in the absence Myc get only a small boost when Myc is present.

Inactivation of SUMO-activating enzyme (SAE1 / SAE2) 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

During the discovery of Myc gene, it was realized that chromosomes that reciprocally 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 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.

Interactions

Myc has been shown to interact with:

• ACTL6A
• BRCA1
• Bcl-2
• Cyclin T1
• CHD8.
• DNMT3A
• EP400
• GTF2I
• HTATIP
• let-7
• MAPK1
• MAPK8
• MAX
• MLH1
• MYCBP2
• MYCBP
• NMI
• NFYB
• NFYC
• P73
• PCAF
• PFDN5
• RuvB-like 1
• SAP130
• SMAD2
• SMAD3
• SMARCA4
• SMARCB1
• SUPT3H
• TIAM1
• TADA2L
• TAF9
• TFAP2A
• TRRAP
• WDR5
• YY1 and
• ZBTB17.

Overview of signal transduction pathways involved in apoptosis.

See also

Myc-tag

External links

• The Myc Protein
• NCBI Human Myc protein
• Myc cancer gene
• myc Proto-Oncogene Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
• Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4
• Drosophila Myc - The Interactive Fly
• FactorBook C-Myc