Myc

Last updated
MYC proto-oncogene, bHLH transcription factor
Identifiers
Symbol MYC
Alt. symbolsc-Myc, v-myc
NCBI gene 4609
HGNC 7553
OMIM 190080
RefSeq NM_001354870.1
UniProt P01106
Other data
Locus Chr. 8 q24.21
Wikidata Q20969939
Search for
Structures Swiss-model
Domains InterPro
MYCL proto-oncogene, bHLH transcription factor
Identifiers
Symbol MYCL
Alt. symbolsLMYC, MYCL1, bHLHe38, L-Myc, v-myc
NCBI gene 4610
HGNC 7555
OMIM 164850
RefSeq NM_005376
UniProt P12524
Other data
Locus Chr. 1 p34.2
Wikidata Q18029714
Search for
Structures Swiss-model
Domains InterPro
MYCN proto-oncogene, bHLH transcription factor
Identifiers
Symbol MYCN
NCBI gene 4613
HGNC 7559
OMIM 164840
RefSeq NM_005378
UniProt V
Other data
Locus Chr. 2 p24.3
Wikidata Q14906753
Search for
Structures Swiss-model
Domains InterPro

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 (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.

Contents

In cancer, c-myc is often constitutively (persistently) expressed. This leads to the increased expression of many genes, some of which are involved in cell proliferation, contributing to the formation of cancer. [1] A common human translocation involving c-myc is critical to the development of most cases of Burkitt lymphoma. [2] Constitutive upregulation of Myc genes have also been observed in carcinoma of the cervix, colon, breast, lung and stomach. [1]

Myc is thus viewed as a promising target for anti-cancer drugs. [3] Unfortunately, Myc possesses several features that have rendered it difficult to drug to date, such that any anti-cancer drugs aimed at inhibiting Myc may continue to require perturbing the protein indirectly, such as by targeting the mRNA for the protein rather than via a small molecule that targets the protein itself. [4] [5]

c-Myc also plays an important role in stem cell biology and was one of the original Yamanaka factors used to reprogram somatic cells into induced pluripotent stem cells. [6]

In the human genome, C-myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes [7] through binding on enhancer box sequences (E-boxes).

In addition to its role as a classical transcription factor, N-myc may recruit histone acetyltransferases (HATs). This allows it to regulate global chromatin structure via histone acetylation. [8]

Discovery

The Myc family was first established after discovery of homology between an oncogene carried by the Avian virus, Myelocytomatosis (v-myc; P10395 ) and a human gene over-expressed in various cancers, cellular Myc (c-Myc).[ citation needed ] Later, discovery of further homologous genes in humans led to the addition of n-Myc and l-Myc to the family of genes. [9]

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 [t(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 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 proteins are transcription factors that activate expression of many pro-proliferative genes through binding enhancer box sequences (E-boxes) and recruiting histone acetyltransferases (HATs). Myc is thought to function by upregulating transcript elongation of actively transcribed genes through the recruitment of transcriptional elongation factors. [10] 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. [11] This activity could contribute to DNA amplification in cancer cells. [12]

Myc is activated upon various mitogenic signals such as serum stimulation or by Wnt, Shh and EGF (via the MAPK/ERK pathway). [13] 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. Nucleotide metabolism genes are upregulated by Myc, [14] which are necessary for Myc induced proliferation [15] or cell growth. [16]

There have been several studies that have clearly indicated Myc's role in cell competition. [17]

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. [18] In B cells, Myc acts as a classical oncogene by regulating a number of pro-proliferative and anti-apoptotic pathways, this also includes tuning of BCR signaling and CD40 signaling in regulation of microRNAs (miR-29, miR-150, miR-17-92). [19]

c-Myc induces MTDH(AEG-1) gene expression and in turn itself requires AEG-1 oncogene for its expression.

Myc-nick

Myc-Nick Myc-Nick.pdf
Myc-Nick

Myc-nick is a cytoplasmic form of Myc produced by a partial proteolytic cleavage of full-length c-Myc and N-Myc. [20] 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.

Clinical significance

A large body of evidence shows that Myc genes and proteins are highly relevant for treating tumors. [9] 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. [6]

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. [21]

Amplification of the MYC gene was found in a significant number of epithelial ovarian cancer cases. [22] In TCGA datasets, the amplification of Myc occurs in several cancer types, including breast, colorectal, pancreatic, gastric, and uterine cancers. [23]

In the experimental transformation process of normal cells into cancer cells, the MYC gene can cooperate with the RAS gene. [24] [25]

Expression of Myc is highly dependent on BRD4 function in some cancers. [26] [27] BET inhibitors have been used to successfully block Myc function in pre-clinical cancer models and are currently being evaluated in clinical trials. [28]

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. [29] Changes in the expression of such RNAs can potentially be used to develop targeted tumor therapy.

Animal models

In Drosophila Myc is encoded by the diminutive locus, (which was known to geneticists prior to 1935). [30] Classical diminutive alleles resulted in a viable animal with small body size. Drosophila has subsequently been used to implicate Myc in cell competition, [31] endoreplication, [32] and cell growth. [33]

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 (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 (CML) cells. Targeting Myc and p53 proteins with drugs gave positive results on mice with CML. [34] [35]

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. [36] In hematopoietic stem cells, Myc controls the balance between self-renewal and differentiation. [37]

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. [38]

Interactions

Myc has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis. Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis.

See also

Related Research Articles

<span class="mw-page-title-main">Oncogene</span> Gene that has the potential to cause cancer

An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

<span class="mw-page-title-main">Oct-4</span> Mammalian protein found in Homo sapiens

Oct-4, also known as POU5F1, is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells. As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.

<span class="mw-page-title-main">Protein c-Fos</span> Mammalian protein found in Homo sapiens

Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the FOS gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV. It is a part of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2. It has been mapped to chromosome region 14q21→q31. c-Fos encodes a 62 kDa protein, which forms heterodimer with c-jun, resulting in the formation of AP-1 complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression. It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.

<span class="mw-page-title-main">N-Myc</span> Protein-coding gene in the species Homo sapiens

N-myc proto-oncogene protein also known as N-Myc or basic helix-loop-helix protein 37 (bHLHe37), is a protein that in humans is encoded by the MYCN gene.

<span class="mw-page-title-main">CTCF</span> Transcription factor

Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the CTCF gene. CTCF is involved in many cellular processes, including transcriptional regulation, insulator activity, V(D)J recombination and regulation of chromatin architecture.

mir-17 microRNA precursor family

The miR-17 microRNA precursor family are a group of related small non-coding RNA genes called microRNAs that regulate gene expression. The microRNA precursor miR-17 family, includes miR-20a/b, miR-93, and miR-106a/b. With the exception of miR-93, these microRNAs are produced from several microRNA gene clusters, which apparently arose from a series of ancient evolutionary genetic duplication events, and also include members of the miR-19, and miR-25 families. These clusters are transcribed as long non-coding RNA transcripts that are processed to form ~70 nucleotide microRNA precursors, that are subsequently processed by the Dicer enzyme to give a ~22 nucleotide products. The mature microRNA products are thought to regulate expression levels of other genes through complementarity to the 3' UTR of specific target messenger RNA.

<span class="mw-page-title-main">MYC</span> Protein-coding gene in the species Homo sapiens

MYC proto-oncogene, bHLH transcription factor is a protein that in humans is encoded by the MYC gene which is a member of the myc family of transcription factors. The protein contains basic helix-loop-helix (bHLH) structural motif.

<span class="mw-page-title-main">MYBL2</span> Protein-coding gene in the species Homo sapiens

Myb-related protein B is a protein that in humans is encoded by the MYBL2 gene.

<span class="mw-page-title-main">MTA1</span> Protein-coding gene in the species Homo sapiens

Metastasis-associated protein MTA1 is a protein that in humans is encoded by the MTA1 gene. MTA1 is the founding member of the MTA family of genes. MTA1 is primarily localized in the nucleus but also found to be distributed in the extra-nuclear compartments. MTA1 is a component of several chromatin remodeling complexes including the nucleosome remodeling and deacetylation complex (NuRD). MTA1 regulates gene expression by functioning as a coregulator to integrate DNA-interacting factors to gene activity. MTA1 participates in physiological functions in the normal and cancer cells. MTA1 is one of the most upregulated proteins in human cancer and associates with cancer progression, aggressive phenotypes, and poor prognosis of cancer patients.

<span class="mw-page-title-main">KLF4</span> Protein-coding gene in the species Homo sapiens

Kruppel-like factor 4 is a member of the KLF family of zinc finger transcription factors, which belongs to the relatively large family of SP1-like transcription factors. KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, including colorectal cancer. It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2. It has two nuclear localization sequences that signals it to localize to the nucleus. In embryonic stem cells (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells (MSCs).

<span class="mw-page-title-main">SOX2</span> Transcription factor gene of the SOX family

SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.

<span class="mw-page-title-main">MAX (gene)</span> Protein-coding gene in the species Homo sapiens

MAX is a gene that in humans encodes the MAX transcription factor.

<span class="mw-page-title-main">MXI1</span> Protein-coding gene in humans

MAX-interacting protein 1 is a protein that in humans is encoded by the MXI1 gene.

<span class="mw-page-title-main">ZBTB17</span> Protein-coding gene in the species Homo sapiens

Zinc finger and BTB domain-containing protein 17 is a protein that in humans is encoded by the ZBTB17 gene.

<span class="mw-page-title-main">MYCL</span> Protein-coding gene in the species Homo sapiens

L-myc-1 proto-oncogene protein is a protein that in humans is encoded by the MYCL1 gene.

<span class="mw-page-title-main">N-myc-interactor</span> Protein-coding gene in the species Homo sapiens

N-myc-interactor also known as N-myc and STAT interactor is a protein that in humans is encoded by the NMI gene.

<span class="mw-page-title-main">MTDH</span> Protein-coding gene in the species Homo sapiens

Metadherin, also known as protein LYRIC or astrocyte elevated gene-1 protein (AEG-1) is a protein that in humans is encoded by the MTDH gene.

mir-22

In molecular biology mir-22 microRNA is a short RNA molecule. MicroRNAs are an abundant class of molecules, approximately 22 nucleotides in length, which can post-transcriptionally regulate gene expression by binding to the 3' UTR of mRNAs expressed in a cell.

<span class="mw-page-title-main">GLIS1</span> Protein-coding gene

Glis1 is gene encoding a Krüppel-like protein of the same name whose locus is found on Chromosome 1p32.3. The gene is enriched in unfertilised eggs and embryos at the one cell stage and it can be used to promote direct reprogramming of somatic cells to induced pluripotent stem cells, also known as iPS cells. Glis1 is a highly promiscuous transcription factor, regulating the expression of numerous genes, either positively or negatively. In organisms, Glis1 does not appear to have any directly important functions. Mice whose Glis1 gene has been removed have no noticeable change to their phenotype.

<span class="mw-page-title-main">Transcriptional amplification</span>

In genetics, transcriptional amplification is the process in which the total amount of messenger RNA (mRNA) molecules from expressed genes is increased during disease, development, or in response to stimuli.

References

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