MYC (MYC proto-oncogene, bHLH transcription factor)

2017-08-01   Anwar N Mohamed 

Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA;


Atlas Image
MYC (8q24) in normal cells: PAC 944B18 (top) and PAC 968N11 (below) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Atlas Image
MYC (MYC proto-oncogene, bHLH transcription factor) Hybridization with Vysis LSI MYC break apart and LSY MYC probe (Abbott Molecular, US) showing the gene on 8q24.21 - Courtesy Adriana Zamecnikova.


Review the structure, function, and role of CMYC gene in tumorigenesis



CMYC is composed of three exons spanning over 4 kb with the second and third exons encoding most MYC protein. These two exons have at least 70% sequence homology among species. However, exon1 is untranslated whose sequence is not as well conserved through evolution. The exon1 has been postulated to play a role in translational control and mRNA stability. There are four MYC transcriptional promoters. In normal cells, promoter P2 contributes to approximately 75% of total MYC transcripts while P1 accounts for most the remaining 25% transcripts (Dang CV 2012).


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.



439 amino acids and 48 kDa in the p64; 454 amino acids in the p67 (15 additional amino acids in N-term; contains from N-term to C-term: a transactivation domain, an acidic domain, a nuclear localization signal, a basic domain, an helix-loop-helix motif, and a leucin zipper; DNA binding protein.


Expressed in almost all proliferating cells in embryonic and adult tissues; in adult tissues, expression correlates with cell proliferation; abnormally high expression is found in a wide variety of human cancers.


located predominantly in the nucleus.
The myc protein contains an unstructured N-terminal transcriptional regulatory domain followed by a nuclear localization signal and a C-terminal region with a basic DNA-binding domain tied to a helix-loop-helix-leucine zipper (bHLHZip) dimerization motif. The bHLHzip motif of MYC dimerizes with the MAX, which is a prerequisite for specific binding to DNA at E-box sequences (5-CA(C/T)G(T/C)G-3) (Dang 2012). Upon DNA binding the MYC/MAX heterodimer recruits co-factors, which mediate multiple effects of MYC on gene expression in a context-dependent manner. This dimerization process is essential for induction of cell cycle progression, apoptosis, and transformation suggesting that MYC exerts its oncogenic effects by transactivation of target genes via E-boxes (Amati B, Land H, 1994; Grandori C et al 2000). The coding exons of MYC encode for the N-terminal region which has a transcriptional regulatory domain, a region that contains conserved MYC Boxes I and II, followed by MYC Box III and IV, and a nuclear targeting sequence. The N-terminal region will bind with co-activator complexes, making MYC acts as the transcription or repression factor (Cowling et al 2006).
In normal cells, MYC is tightly regulated by mitotic and developmental signals, and in turn, it regulates the expression of downstream target genes. Both MYC mRNA and protein have very short half-lives in normal cells (20-30 minutes each). Without appropriate positive regulatory signals, MYC protein levels are low and insufficient to promote cellular proliferation. In addition, MYC protein is rapidly degraded by the ubiquitin-linked proteasome machinery. The short-life and instability of MYC protein and mRNA together would seem to be an effective safeguard mechanism of MYC regulation (Herrick and Ross et al, 1994). However, these controls are lost in cancer cells, resulting in aberrantly high levels of MYC protein. In its physiological role, MYC is broadly expressed during embryogenesis and in tissue with high proliferative capacity such as skin epidermis and gut. Its expression strongly correlates with cell proliferation.


MYC functions as a transcriptional regulator, capable to induce or repress the expression of a large number of genes, which are thought to mediate its biological functions (Adhikary and Eilers 2005). MYC protein cannot form homodimers, but it binds to MAX that is an obligate heterodimeric partner for MYC in mediating its functions. The MYC-MAX complex is a potent activator of transcription for a critical set of cellular target genes. Initially, two additional partners for Max had been identified, MXI1 and MXD1 (Mad1). Two more Max-interacting proteins, MXD3 (Mad3) and MXD4 (Mad4), which behave similarly to MXD1 have been reported. The transcription activation is mediated exclusively by MYC-MAX complexes, whereas MAX-MXD1 and MAX-MXI1 complexes mediate transcription repression through identical binding sites. Max expression is not highly regulated and its protein is very stable; in contrast, MXD1 protein appears to have a short half-life and to be highly regulated (Amati and Land, 1994). MXI1 protein is also regulated. MYC-MAX heterodimers activate transcription through interactions with transcriptional coactivators ( TRRAP, ACTL6A (BAF53)) and their associated histone acetyltransferases and/or ATPase/helicases, resulting in transition from the G0/1 phase to the S phase (Nilsson and Cleveland, 2003). Several studies have established that MAX is essential for MYC-mediated gene transactivation, transformation, cell cycle progression and apoptosis. On the other hand, overexpression of MXI1 and MXD1 can antagonize MYC activity in cellular transformation assays and proliferation and can diminish the malignant phenotype of tumor cells. MXD1 can also inhibit apoptosis and reverse the differentiation blocking effect of MYC in leukemia cells. (Dang 2012). These findings are consistent with the concept that MXD1 and MXI1 suppress MYC function. In addition to interacting with proteins involved in transcription regulation, MYC also interacts with enzymes controlling histone methylation.
Target Genes Thousands of MYC target genes have been identified by following mRNA levels in experimentally controlled activation of the MYC gene (Menssen and Hermeking 2002). In general, genes targeted by MYC include mediators of metabolism, biosynthesis, and cell cycle progression, such that aberrant MYC expression is associated with uncontrolled cell growth, division, and metastasis, whereas loss or inhibition of MYC expression hinders growth, promotes differentiation, and sensitizes cells to DNA damage (Miller 2012; Hsieh 2015). Different target genes are regulated under specific conditions for specific cell types. Some of the most biologically important targets are CCND2 (cyclin D2), and cyclin-dependent kinases (CDKs), resulting in accelerated cell cycling; down-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) with consequent up-regulation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/ MTOR) pathway; and stabilization of the proapoptotic protein and tumor suppressor TP53, (Hoffman and Liebermann 2008; Dang 2012) which can bypass the apoptotic BCL2 program. MYC, on the other hand, activates many ribosomal protein genes including RPL23, which binds to and retains NPM1 in the nucleolus, thereby inhibiting PIAS2 (Miz-1) activity (Wanzel, 2008). MYC itself is modulated by NPM1, which acts as a positive MYC coactivator (Schneider A 1997; Grandori C et al., 2005; Li Z, et al 2008).
MYC-targeted gene network also contains non-protein coding targets; among those are microRNAs (miRNAs). The miRNAs are 18- 22 nucleotides non-coding RNAs that negatively regulate gene expression at the post-transcriptional level via binding to 3-UTRs of target mRNAs and mediate translational repression or mRNA degradation. Some miRNA function as an oncogene while others behave as tumor suppressor gene, in a cell-typed manner. Growing evidences have suggested that MYC regulates the expression of a number of miRNAs, resulting in widespread repression of miRNA and, at the same time, MYC being subjected to regulation by miRNAs, leading to sustained MYC activity and the corresponding MYC downstream pathways (Chang et al, 2008). Thus, these combined effects of MYC overexpression and downregulation of miRNAs play a central regulatory role in the MYC oncogenic pathways. For example, MYC upregulates expression of miR-17-92 clusters a set of oncogenic miRNAs, which contains six mature miRNAs. Recently, miR-19 was identified as the key oncogenic component of this cluster (Tao et al 2014; Koh 2016). Overexpression of miR-17-92 is observed in a large fraction of human cancers, including carcinomas of the breast, lung, and colon; medulloblastomas; neuroblastomas and B-cell lymphoma. The miR17-92 is commonly amplified at 13q31 in several subtypes of aggressive lymphomas. Its oncogenic function is reflected by down-regulation of PTEN, TP53 and E2F1, causing the activation of the PI3K/AKT pathway and inhibiting cellular apoptosis. The functional interaction between miR-17`92 and MYC is further emphasized by the finding that MYC is a potent transcriptional activator of miR-17-92 (ODonnell et al. 2005), thus suggesting that miR-17-92 may contribute to the oncogenic properties of MYC. Another MYC-induced miRNA, MIR22, was recently shown to act as a potent proto-oncogenic miRNA by genome-wide deregulation of the epigenetic state through inhibition of methylcytosine dioxygenase TET proteins. In addition, MIR22 was characterized as a key regulator of self-renewal in the hematopoietic system. MYC also represses several miRNAs with tumor suppressor function such as MIR15A/ MIR16-1 and miR-34 that regulate apoptosis by targeting BCL2 and TP53 respectively. Likewise MYC is negatively regulated by several miRNAs such as miR-34 and MIR494. The auto functional interaction between MYC and miRNAs target genes maintains persistent expression of MYC, thus promoting the malignant phenotype (Tao et al 2014; Jackstadt 2015).
Furthermore, over expression of MYC can induce apoptosis. The apoptosis triggered or sensitized by MYC can be either TP53-dependent or TP53 independent, determined by the cell type and apoptotic trigger. The mechanisms of MYC-mediated apoptosis may involve several pathways. Overexpression of MYC increases DNA replication and possibly results in DNA damage that, in turn, triggers a TP53-mediated response leading to apoptosis, in some cell types (Hoffman and Libermann, 2008). As well, MYC expression seems to downregulate antiapoptotic proteins such as BCL2 or BCL2L1 (Bcl-XL) and upregulate pro-apoptotic elements such as BCL2L11 (BIM).
MYC also plays an important role in mitochondrial biogenesis. Large scale studies of gene expression in rat and human systems first suggested that MYC overexpression can induce nuclear encoded mitochondrial genes. In addition, MYC has been shown to bind to the promoters of genes encoding proteins involved in mitochondrial function. Using an inducible MYC-dependent human B cell model of cell proliferation it was shown that mitochondrial biogenesis is completely dependent on MYC expression. Moreover, the genes involved with mitochondrial biogenesis are among the MYC target genes most highly induced (Gao et al 2009).

Implicated in

Top note
MYC Deregulation
The expression of MYC is deregulated in cancer by several different mechanisms, including chromosomal translocations, amplifications, point mutations, epigenetic reprogramming, enhanced translation and increased protein stability. In most cases these alterations lead to a constitutive expression of intact MYC protein, which is normally only expressed during certain phases of the cell cycle. In Burkitt lymphoma (BL), the MYC oncogene is activated through a reciprocal t(8;14) or its variant which juxtaposes MYC/8q24 to enhancer of the immunoglobulin (Ig) heavy Chain (IGH) locus on chromosome 14q32 or the kappa or lambda light chain locus on chromosome 2 or 22. There are three main translocation breakpoints in MYC; class I breakpoints are within the exon 1 and first intron of MYC; class II breakpoints are located at the 5 end of the MYC, and usually within a few kilobases of exon 1; and the class III breakpoints are distant from MYC itself, and can be more than 100 kb away. Endemic BL typically shows class II translocation breakpoints in MYC while the sporadic BL often exhibits class I breakpoints of MYC. The t(8;14) or its variant is considered as an initiative event in BL. The MYC/8q24 translocations may also occur as secondary events in non-BL lymphomas such as diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma (Cai et al, 2015; Nguyen L, et al 2017). Secondary MYC translocation is associated with a complex karyotype and most often confer aggressive clinical behavior and poor outcome. Recently, B-cell large cell lymphoma with MYC and BCL2 or/and BCL6 rearrangements so called double hit or triple hit lymphoma are recognized by the 2016 revision of WHO as a subset of a very aggressive lymphoma (Petrich 2014). >
Amplification of MYC gene has been shown in both hematopoietic and non-hematopoietic tumors, including lung, breast, colon, and prostate cancers. Insertional mutagenesis is seen in retrovirus-induced tumors, such as avian leucosis virus (ALV)-induced hematopoietic tumors, in which the proviral enhancer is integrated upstream of the MYC gene and leads to its overexpression. MYC overexpression may also occur because of post-translational modifications. MYC protein overexpression as a result of point mutations in N-terminal domain is also frequent. The most recurrently mutated residue is Thr-58, found in lymphoma. Normally, the phosphorylation of Thr-58 can control MYC degradation and mutation causing increase of MYC protein half-life in lymphoma (Cai et al 2017). Detection of MYC rearrangement is important in the diagnosis of BL and as a prognostic marker in other aggressive B-cell lymphomas. There are several techniques to detect MYC deregulation including conventional cytogenetics, fluorescence in situ hybridization (FISH), and immunohistochemistry. In clinical laboratory, FISH is being most frequently used approach (Figure 2) >
MYC as therapeutic target
MYC is documented to be involved broadly in many cancers, in which its expression is estimated to be elevated or deregulated in up to 70% of human cancers. Overexpression of MYC protein is not only to drive tumor initiation and progression, but is also essential for tumor maintenance. Furthermore, growth arrest, apoptosis and differentiation occur upon reduction in MYC levels. These features make MYC molecule a highly attractive target for cancer therapy. However, the lack of deep pocket in the structure of MYC protein makes the traditionally small molecule inhibitors are not feasible. For this reason, other alternative strategies are proposed. One approach suggests that the disruption of the MYC/MAX binding site can be a strategy for the inactivation of MYC function in neoplastic cells. Such an approach was already applied and different small molecule inhibitors that can specifically target MYC were already successfully produced. Other approach is based on the inhibition of MYC/MAX dimers binding to E-boxes in the promoters of different MYC target genes. Other groups have focused on transcriptional inhibition of the MYC gene. Preliminary evidence from experiments using MYC antisense oligonucleotides has been encouraging, but has not translated into effective clinical treatments ( Koh 2016).
Atlas Image
FISH using MYC/IGH/CEP8 triple color dual fusion DNA probe set, showing dual fusion pattern, consistent with t(8;14)(q24;q32) [left] in a case with Burkitt lymphoma; MYC amplification in acute myeloid leukemia [right] - Anwar N. Mohamed.
MYC gene encodes a multifunctional, nuclear phosphoprotein that controls a variety of cellular functions, including cell cycle, cell growth, apoptosis, cellular metabolism and biosynthesis, adhesion, and mitochondrial biogenesis. MYC has been shown to be an essential global transcription factor capable of either promoting or repressing the expression of a massive array of genes, accounting for >15% of the human genome, commonly referred to as the "MYC signature" (Knoepfler 2007). MYC is among the most frequently affected gene in human cancers, overexpressed in most human cancers and contributes to the cause of at least 40% of tumors. Dysregulation of MYC expression results through various types of genetic alterations leading to a constitutive activity of MYC in various cancers (Dang et al, 2006).


Atlas Image


Pubmed IDLast YearTitleAuthors
160641382005Transcriptional regulation and transformation by Myc proteins.Adhikary S et al
81935301994Myc-Max-Mad: a transcription factor network controlling cell cycle progression, differentiation and death.Amati B et al
264164272015MYC-driven aggressive B-cell lymphomas: biology, entity, differential diagnosis and clinical management.Cai Q et al
180660652008Widespread microRNA repression by Myc contributes to tumorigenesis.Chang TC et al
167051732006A conserved Myc protein domain, MBIV, regulates DNA binding, apoptosis, transformation, and G2 arrest.Cowling VH et al
224643212012MYC on the path to cancer.Dang CV et al
169049032006The c-Myc target gene network.Dang CV et al
192190262009c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.Gao P et al
157230542005c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I.Grandori C et al
81147421994The half-life of c-myc mRNA in growing and serum-stimulated cells: influence of the coding and 3' untranslated regions and role of ribosome translocation.Herrick DJ et al
189559732008Apoptotic signaling by c-MYC.Hoffman B et al
262775432015MYC and metabolism on the path to cancer.Hsieh AL et al
247270922015MicroRNAs as regulators and mediators of c-MYC function.Jackstadt R et al
175455792007Myc goes global: new tricks for an old oncogene.Knoepfler PS et al
267786682016Targeting MYC in cancer therapy: RNA processing offers new opportunities.Koh CM et al
190331982008Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation.Li Z et al
119839162002Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes.Menssen A et al
230713562012c-Myc and cancer metabolism.Miller DM et al
283791892017The Role of c-MYC in B-Cell Lymphomas: Diagnostic and Molecular Aspects.Nguyen L et al
146634792003Myc pathways provoking cell suicide and cancer.Nilsson JA et al
159447092005c-Myc-regulated microRNAs modulate E2F1 expression.O'Donnell KA et al
250605882014MYC-associated and double-hit lymphomas: a review of pathobiology, prognosis, and therapeutic approaches.Petrich AM et al
93082371997Association of Myc with the zinc-finger protein Miz-1 defines a novel pathway for gene regulation by Myc.Schneider A et al
243949402014c-MYC-miRNA circuitry: a central regulator of aggressive B-cell malignancies.Tao J et al
191604852008A ribosomal protein L23-nucleophosmin circuit coordinates Mizl function with cell growth.Wanzel M et al

Other Information

Locus ID:

NCBI: 4609
MIM: 190080
HGNC: 7553
Ensembl: ENSG00000136997


dbSNP: 4609
ClinVar: 4609
TCGA: ENSG00000136997


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
ErbB signaling pathwayKEGGko04012
Cell cycleKEGGko04110
Wnt signaling pathwayKEGGko04310
TGF-beta signaling pathwayKEGGko04350
Jak-STAT signaling pathwayKEGGko04630
Colorectal cancerKEGGko05210
Endometrial cancerKEGGko05213
Thyroid cancerKEGGko05216
Bladder cancerKEGGko05219
Chronic myeloid leukemiaKEGGko05220
Acute myeloid leukemiaKEGGko05221
Small cell lung cancerKEGGko05222
MAPK signaling pathwayKEGGhsa04010
ErbB signaling pathwayKEGGhsa04012
Cell cycleKEGGhsa04110
Wnt signaling pathwayKEGGhsa04310
TGF-beta signaling pathwayKEGGhsa04350
Jak-STAT signaling pathwayKEGGhsa04630
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Endometrial cancerKEGGhsa05213
Thyroid cancerKEGGhsa05216
Bladder cancerKEGGhsa05219
Chronic myeloid leukemiaKEGGhsa05220
Acute myeloid leukemiaKEGGhsa05221
Small cell lung cancerKEGGhsa05222
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Thyroid hormone signaling pathwayKEGGhsa04919
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Central carbon metabolism in cancerKEGGhsa05230
Central carbon metabolism in cancerKEGGko05230
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by NOTCH1 in CancerREACTOMER-HSA-2644603
Signaling by NOTCH1 PEST Domain Mutants in CancerREACTOMER-HSA-2644602
Constitutive Signaling by NOTCH1 PEST Domain MutantsREACTOMER-HSA-2644606
Signaling by NOTCH1 HD+PEST Domain Mutants in CancerREACTOMER-HSA-2894858
Constitutive Signaling by NOTCH1 HD+PEST Domain MutantsREACTOMER-HSA-2894862
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Signal TransductionREACTOMER-HSA-162582
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK6/MAPK4 signalingREACTOMER-HSA-5687128
Signaling by TGF-beta Receptor ComplexREACTOMER-HSA-170834
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimerREACTOMER-HSA-2173793
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcriptionREACTOMER-HSA-2173796
Signaling by NOTCHREACTOMER-HSA-157118
Signaling by NOTCH1REACTOMER-HSA-1980143
NOTCH1 Intracellular Domain Regulates TranscriptionREACTOMER-HSA-2122947
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Formation of the beta-catenin:TCF transactivating complexREACTOMER-HSA-201722
Binding of TCF/LEF:CTNNB1 to target gene promotersREACTOMER-HSA-4411364
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G1/S TransitionREACTOMER-HSA-69206
Cyclin E associated events during G1/S transitionREACTOMER-HSA-69202
Cyclin A:Cdk2-associated events at S phase entryREACTOMER-HSA-69656
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factorsREACTOMER-HSA-8864260
TFAP2 (AP-2) family regulates transcription of cell cycle factorsREACTOMER-HSA-8866911
Ub-specific processing proteasesREACTOMER-HSA-5689880
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
159447092005c-Myc-regulated microRNAs modulate E2F1 expression.1081
181571152008Reprogramming of human somatic cells to pluripotency with defined factors.1046
192190262009c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.736
204349842010c-Myc regulates transcriptional pause release.623
180660652008Widespread microRNA repression by Myc contributes to tumorigenesis.525
201737402010miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis.489
219493972011Targeting MYC dependence in cancer by inhibiting BET bromodomains.426
200108082010HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer.391
123602792002c-MYC: more than just a matter of life and death.340
174821312007HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.333


Anwar N Mohamed

MYC (MYC proto-oncogene, bHLH transcription factor)

Atlas Genet Cytogenet Oncol Haematol. 2017-08-01

Online version:

Historical Card

2000-08-01 MYC (MYC proto-oncogene, bHLH transcription factor) by  Niels B Atkin 

Department of Cancer Research, Mount Vernon Hospital, Northwood, Middlesex, UK