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''Myc'' is a family of regulator genes and proto-oncogenes that
code In communications and information processing, code is a system of rules to convert information—such as a letter, word, sound, image, or gesture—into another form, sometimes shortened or secret, for communication through a communicati ...
for
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes referred to as ''MYC'') was the first gene to be discovered in this family, due to homology with the viral gene ''v-myc''. In
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, ''c-myc'' is often constitutively (persistently) expressed. This leads to the increased expression of many genes, some of which are involved in
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation r ...
, contributing to the formation of cancer. A common human translocation involving ''c-myc'' is critical to the development of most cases of
Burkitt lymphoma Burkitt lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Afric ...
. 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 The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the ...
, ''C-myc'' is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on enhancer box sequences (
E-box An E-box (enhancer box) is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG (where N can ...
es). In addition to its role as a classical transcription factor, ''N-myc'' may recruit
histone acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
s (HATs). 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 (''v-myc''; ) and a human gene over-expressed in various cancers, cellular Myc (''c-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 Burkitt lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa. ...
. In Burkitt's lymphoma, cancer cells show
chromosomal translocation In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal transl ...
s, most commonly between chromosome 8 and chromosome 14 (8;14) This causes ''c-Myc'' to be placed downstream of the highly active immunoglobulin (Ig) 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 (basic helix-loop-helix) and LZ ( leucine zipper) 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 In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
contains an IRES (internal ribosome entry site) that allows the RNA to be translated into protein when
5' cap In molecular biology, the five-prime cap (5′ cap) is a specially altered nucleotide on the 5′ end of some primary transcripts such as precursor messenger RNA. This process, known as mRNA capping, is highly regulated and vital in the creation ...
-dependent translation is inhibited, such as during viral infection.


Function

Myc proteins are
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s that activate expression of many pro-proliferative genes through binding enhancer box sequences (
E-box An E-box (enhancer box) is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG (where N can ...
es) and recruiting
histone acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
s (HATs). Myc is thought to function by upregulating transcript elongation of actively transcribed genes through the recruitment of transcriptional elongation factors. It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300
co-activator A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA ...
, 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 (via the
MAPK/ERK pathway The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling ...
). 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 Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation r ...
(upregulates cyclins, downregulates p21), but it also plays a very important role in regulating
cell growth Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater th ...
(upregulates ribosomal RNA and proteins),
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
(downregulates
Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosi ...
), differentiation, and
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...
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 B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...
proliferation, and gain of MYC has been associated with B cell malignancies and their increased aggressiveness, including histological transformation. In B cells, Myc acts as a classical oncogene by regulating a number of pro-proliferative and anti-apoptotic pathways, this also includes tunning of BCR signaling and CD40 signaling is regulation of microRNAs (miR-29, miR-150, miR-17-92). c-Myc induces MTDH(AEG-1) 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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein i ...
of Myc (containing the
DNA binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...
) is degraded, while Myc-nick, the
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
segment 298-residue segment remains in the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
. Myc-nick contains binding domains for
histone acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
s and for
ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquit ...
s. 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 Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...
.
Ectopic expression Ectopic is a word used with a prefix, ecto, meaning “out of place.” Ectopic expression is an abnormal gene expression in a cell type, tissue type, or developmental stage in which the gene is not usually expressed. The term ectopic expression is ...
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 ( SAE1 / SAE2) in the presence of Myc hyperactivation results in mitotic catastrophe and cell death in cancer cells. Hence inhibitors of
SUMOylation In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (sometimes w ...
may be a possible treatment for cancer. Amplification of the MYC gene was found in a significant number of epithelial
ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...
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 Bromodomain-containing protein 4 is a protein that in humans is encoded by the ''BRD4'' gene. BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT. BRD4, similar to other BET fami ...
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. MYC expression is controlled by a wide variety of noncoding RNAs, including miRNA, lncRNA, and circRNA. Some of these RNAs have been shown to be specific for certain types of human tissues and tumors. Changes in the expression of such RNAs can potentially be used to develop targeted tumor therapy.


Animal models

In
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
Myc is encoded by the diminutive locus, (which was known to geneticists prior to 1935). 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 An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of th ...
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 (liver, breast) 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 (such as AMPK, more oxygen consumption, more body movements, etc.). 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 (calorie restriction) ames dwarf, rapamycin, metformin and resveratrol. One study found that Myc and p53 genes were key to the survival of
chronic myeloid leukaemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulati ...
(CML) cells. Targeting Myc and p53 proteins with drugs gave positive results on mice with CML.


Relationship to stem cells

''Myc'' genes play a number of normal roles in stem cells including pluripotent stem cells. In neural stem cells, N-Myc promotes a rapidly proliferative stem cell and precursor-like state in the developing brain, while inhibiting differentiation. In hematopoietic stem cells, Myc controls the balance between self-renewal and differentiation. ''c-Myc'' plays a major role in the generation of induced pluripotent stem cells (iPSCs). 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 Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with: * ACTL6A *
BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
*
Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosi ...
*
Cyclin T1 Cyclin-T1 is a protein that in humans is encoded by the ''CCNT1'' gene. Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance thro ...
* CHD8 *
DNMT3A DNA (cytosine-5)-methyltransferase 3A is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene. This enzyme is responsible f ...
* EP400 *
GTF2I General transcription factor II-I is a protein that in humans is encoded by the ''GTF2I'' gene. Function This gene encodes a multifunctional phosphoprotein, TFII-I, with roles in transcription and signal transduction. Haploinsuffiency (deletio ...
* HTATIP * let-7 * MAPK1 *
MAPK8 Mitogen-activated protein kinase 8 (also known as JNK1) is a ubiquitous enzyme that in humans is encoded by the ''MAPK8'' gene. Function The protein encoded by this gene is a member of the MAP kinase and JNK family. MAP kinases act as an in ...
* MAX *
MLH1 DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH ...
* MYCBP2 *
MYCBP C-Myc-binding protein is a protein that in humans is encoded by the ''MYCBP'' gene. Function The MYCBP gene encodes a protein that binds to the N-terminal region of MYC (MIM 190080) and stimulates the activation of E box-dependent transcriptio ...
* NMI * NFYB * NFYC * P73 *
PCAF P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53. Structure Several domains of PCAF can act independently or in unison to enable its funct ...
* PFDN5 * RuvB-like 1 * SAP130 * SMAD2 * SMAD3 *
SMARCA4 Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the ''SMARCA4'' gene. Function The protein encoded by this gene is a member of the SWI/SNF family of proteins and ...
*
SMARCB1 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 is a protein that in humans is encoded by the ''SMARCB1'' gene. Function The protein encoded by this gene is part of a complex that relieves repressi ...
* SUPT3H * TIAM1 * TADA2L * TAF9 * TFAP2A * TRRAP * WDR5 *
YY1 YY1 (Yin Yang 1) is a transcriptional repressor protein in humans that is encoded by the YY1 gene. Function YY1 is a ubiquitously distributed transcription factor belonging to the GLI-Kruppel class of zinc finger proteins. The protein is inv ...
and * ZBTB17. * C2orf16


See also

*
Myc-tag A myc tag is a polypeptide protein tag derived from the c-myc gene product that can be added to a protein using recombinant DNA technology. It can be used for affinity chromatography, then used to separate recombinant, overexpressed protein from wil ...
* C-myc mRNA


References


Further reading

* * * * * * * * * * * * * * * * * * * *


External links

* InterPro signatures for protein family: , ,
The Myc Protein

NCBI Human Myc protein

Myc cancer gene
*
Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4


*
PDBe-KB
provides an overview of all the structure information available in the PDB for Human Myc proto-oncogene protein {{Transcription factors, g1 Oncogenes Transcription factors Human proteins