Biology:Myc

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Short description: Family of regulator genes
MYC proto-oncogene, bHLH transcription factor
Identifiers
SymbolMYC
Alt. symbolsc-Myc, v-myc
NCBI gene4609
HGNC7553
OMIM190080
RefSeqNM_001354870.1
UniProtP01106
Other data
LocusChr. 8 q24.21
WikidataQ20969939
MYCL proto-oncogene, bHLH transcription factor
Identifiers
SymbolMYCL
Alt. symbolsLMYC, MYCL1, bHLHe38, L-Myc, v-myc
NCBI gene4610
HGNC7555
OMIM164850
RefSeqNM_005376
UniProtP12524
Other data
LocusChr. 1 p34.2
WikidataQ18029714
MYCN proto-oncogene, bHLH transcription factor
Identifiers
SymbolMYCN
NCBI gene4613
HGNC7559
OMIM164840
RefSeqNM_005378
UniProtV
Other data
LocusChr. 2 p24.3
WikidataQ14906753

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.

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 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.

See also

References

  1. ↑ 1.0 1.1 "Myc". NCBI. https://www.ncbi.nlm.nih.gov/gene/17869. 
  2. ↑ "Sequence analysis of the Myc oncogene involved in the t(8;14)(q24;q11) chromosome translocation in a human leukemia T-cell line indicates that putative regulatory regions are not altered". Proceedings of the National Academy of Sciences of the United States of America 85 (9): 3052–6. May 1988. doi:10.1073/pnas.85.9.3052. PMID 2834731. Bibcode: 1988PNAS...85.3052F. 
  3. ↑ Begley S (2013-01-09). "DNA pioneer James Watson takes aim at cancer establishments". Reuters. https://www.reuters.com/article/us-usa-cancer-watson-idUSBRE90805N20130109. 
  4. ↑ "Therapeutic Inhibition of Myc in Cancer. Structural Bases and Computer-Aided Drug Discovery Approaches". International Journal of Molecular Sciences 20 (1): 120. December 2018. doi:10.3390/ijms20010120. PMID 30597997. 
  5. ↑ "Drugging the 'undruggable' cancer targets". Nature Reviews. Cancer 17 (8): 502–508. August 2017. doi:10.1038/nrc.2017.36. PMID 28643779. 
  6. ↑ 6.0 6.1 "c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells". Cell 151 (1): 68–79. September 2012. doi:10.1016/j.cell.2012.08.033. PMID 23021216. 
  7. ↑ "Pluripotency redux--advances in stem-cell research". The New England Journal of Medicine 357 (15): 1469–72. October 2007. doi:10.1056/NEJMp078126. PMID 17928593. 
  8. ↑ "N-Myc regulates a widespread euchromatic program in the human genome partially independent of its role as a classical transcription factor". Cancer Research 68 (23): 9654–62. December 2008. doi:10.1158/0008-5472.CAN-08-1961. PMID 19047142. 
  9. ↑ 9.0 9.1 "Targeting MYC Proteins for Tumor Therapy". Annual Review of Cancer Biology 4: 61–75. 2020. doi:10.1146/annurev-cancerbio-030518-055826. 
  10. ↑ "MYC and transcription elongation". Cold Spring Harbor Perspectives in Medicine 4 (1): a020990. January 2014. doi:10.1101/cshperspect.a020990. PMID 24384817. 
  11. ↑ "Non-transcriptional control of DNA replication by c-Myc". Nature 448 (7152): 445–51. July 2007. doi:10.1038/nature05953. PMID 17597761. Bibcode: 2007Natur.448..445D. 
  12. ↑ "Stimulation of methotrexate resistance and dihydrofolate reductase gene amplification by c-myc". Oncogene 6 (8): 1453–7. August 1991. PMID 1886715. 
  13. ↑ "Cell-cycle control of c-myc but not c-ras expression is lost following chemical transformation". Cell 36 (2): 241–7. 1984. doi:10.1016/0092-8674(84)90217-4. PMID 6692471. 
  14. ↑ "Global regulation of nucleotide biosynthetic genes by c-Myc". PLOS ONE 3 (7): e2722. July 2008. doi:10.1371/journal.pone.0002722. PMID 18628958. Bibcode: 2008PLoSO...3.2722L. 
  15. ↑ "Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells". Cell Cycle 7 (15): 2392–400. August 2008. doi:10.4161/cc.6390. PMID 18677108. 
  16. ↑ "The Interplay between Myc and CTP Synthase in Drosophila". PLOS Genetics 12 (2): e1005867. February 2016. doi:10.1371/journal.pgen.1005867. PMID 26889675. 
  17. ↑ "Myc-driven endogenous cell competition in the early mammalian embryo". Nature 500 (7460): 39–44. August 2013. doi:10.1038/nature12389. PMID 23842495. Bibcode: 2013Natur.500...39C. 
  18. ↑ "Analysis of C-MYC function in normal cells via conditional gene-targeted mutation". Immunity 14 (1): 45–55. January 2001. doi:10.1016/S1074-7613(01)00088-7. PMID 11163229. 
  19. ↑ "miRiad roles for the miR-17-92 cluster in development and disease". Cell 133 (2): 217–22. April 2008. doi:10.1016/j.cell.2008.04.001. PMID 18423194. 
  20. ↑ "Myc-nick: a cytoplasmic cleavage product of Myc that promotes alpha-tubulin acetylation and cell differentiation". Cell 142 (3): 480–93. August 2010. doi:10.1016/j.cell.2010.06.037. PMID 20691906. 
  21. ↑ "A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis". Science 335 (6066): 348–53. January 2012. doi:10.1126/science.1212728. PMID 22157079. Bibcode: 2012Sci...335..348K. 
  22. ↑ "Comprehensive genomic profiling of epithelial ovarian cancer by next generation sequencing-based diagnostic assay reveals new routes to targeted therapies". Gynecologic Oncology 130 (3): 554–9. September 2013. doi:10.1016/j.ygyno.2013.06.019. PMID 23791828. 
  23. ↑ "Identification of druggable cancer driver genes amplified across TCGA datasets". PLOS ONE 9 (5): e98293. 2014. doi:10.1371/journal.pone.0098293. PMID 24874471. Bibcode: 2014PLoSO...998293C. 
  24. ↑ "Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes". Nature 304 (5927): 596–602. 1983. doi:10.1038/304596a0. PMID 6308472. Bibcode: 1983Natur.304..596L. 
  25. ↑ "Tumor induction by ras and myc oncogenes in fetal and neonatal brain: modulating effects of developmental stage and retroviral dose". Acta Neuropathologica 86 (5): 456–65. 1993. doi:10.1007/bf00228580. PMID 8310796. 
  26. ↑ "Regulation of MYC expression and differential JQ1 sensitivity in cancer cells". PLOS ONE 9 (1): e87003. 2014. doi:10.1371/journal.pone.0087003. PMID 24466310. Bibcode: 2014PLoSO...987003F. 
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  28. ↑ "BET bromodomain inhibition as a therapeutic strategy to target c-Myc". Cell 146 (6): 904–17. September 2011. doi:10.1016/j.cell.2011.08.017. PMID 21889194. 
  29. ↑ "The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer". Biomedicines 9 (8): 921. July 2021. doi:10.3390/biomedicines9080921. PMID 34440124. 
  30. ↑ "Salivary Chromosome Analysis of the White-Facet Region of Drosophila Melanogaster". Genetics 23 (3): 291–9. May 1938. doi:10.1093/genetics/23.3.291. PMID 17246888. 
  31. ↑ "Drosophila myc regulates organ size by inducing cell competition". Cell 117 (1): 107–16. April 2004. doi:10.1016/S0092-8674(04)00214-4. PMID 15066286. 
  32. ↑ "Drosophila dMyc is required for ovary cell growth and endoreplication". Development 131 (4): 775–86. February 2004. doi:10.1242/dev.00932. PMID 14724122. 
  33. ↑ "Drosophila myc regulates cellular growth during development". Cell 98 (6): 779–90. September 1999. doi:10.1016/S0092-8674(00)81512-3. PMID 10499795. PMC 10176494. https://www.zora.uzh.ch/id/eprint/740/1/Johnston_1999.pdf. 
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  39. ↑ 39.0 39.1 39.2 39.3 "BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation". Molecular and Cellular Biology 22 (5): 1307–16. March 2002. doi:10.1128/mcb.22.5.1307-1316.2002. PMID 11839798. 
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  44. ↑ 44.0 44.1 "Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation". The Journal of Biological Chemistry 279 (38): 40209–19. September 2004. doi:10.1074/jbc.M404056200. PMID 15210690. 
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  61. ↑ 61.0 61.1 "Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX". Oncogene 22 (6): 819–25. February 2003. doi:10.1038/sj.onc.1206252. PMID 12584560. 
  62. ↑ "Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc". Science 251 (4998): 1211–7. March 1991. doi:10.1126/science.2006410. PMID 2006410. Bibcode: 1991Sci...251.1211B. 
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  68. ↑ "Differential effects of the widely expressed dMax splice variant of Max on E-box vs initiator element-mediated regulation by c-Myc". Oncogene 18 (15): 2489–98. April 1999. doi:10.1038/sj.onc.1202611. PMID 10229200. 
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  70. ↑ "Identification of a large Myc-binding protein that contains RCC1-like repeats". Proceedings of the National Academy of Sciences of the United States of America 95 (16): 9172–7. August 1998. doi:10.1073/pnas.95.16.9172. PMID 9689053. Bibcode: 1998PNAS...95.9172G. 
  71. ↑ "AMY-1, a novel C-MYC binding protein that stimulates transcription activity of C-MYC". Genes to Cells 3 (8): 549–65. August 1998. doi:10.1046/j.1365-2443.1998.00206.x. PMID 9797456. 
  72. ↑ "Mechanism for the transcriptional repression by c-Myc on PDGF beta-receptor". Journal of Cell Science 114 (Pt 8): 1533–44. April 2001. doi:10.1242/jcs.114.8.1533. PMID 11282029. 
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  75. ↑ 75.0 75.1 75.2 75.3 75.4 75.5 "c-Myc transformation domain recruits the human STAGA complex and requires TRRAP and GCN5 acetylase activity for transcription activation". The Journal of Biological Chemistry 278 (22): 20405–12. May 2003. doi:10.1074/jbc.M211795200. PMID 12660246. 
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  77. ↑ "MM-1, a c-Myc-binding protein, is a candidate for a tumor suppressor in leukemia/lymphoma and tongue cancer". The Journal of Biological Chemistry 276 (48): 45137–44. November 2001. doi:10.1074/jbc.M106127200. PMID 11567024. 
  78. ↑ 78.0 78.1 "Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-beta-mediated induction of the CDK inhibitor p15(Ink4B)". Molecular Cell 9 (1): 133–43. January 2002. doi:10.1016/s1097-2765(01)00430-0. PMID 11804592. 
  79. ↑ "Guanine nucleotide exchange factor, Tiam1, directly binds to c-Myc and interferes with c-Myc-mediated apoptosis in rat-1 fibroblasts". The Journal of Biological Chemistry 278 (7): 5132–40. February 2003. doi:10.1074/jbc.M206733200. PMID 12446731. 
  80. ↑ "Transcriptional activation by Myc is under negative control by the transcription factor AP-2". The EMBO Journal 14 (7): 1508–19. April 1995. doi:10.1002/j.1460-2075.1995.tb07137.x. PMID 7729426. 
  81. ↑ "Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC". Molecular Cell 58 (3): 440–52. May 2015. doi:10.1016/j.molcel.2015.02.028. PMID 25818646. 
  82. ↑ "Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc". Science 262 (5141): 1889–92. December 1993. doi:10.1126/science.8266081. PMID 8266081. Bibcode: 1993Sci...262.1889S. 
  83. ↑ "Repression of p15INK4b expression by Myc through association with Miz-1". Nature Cell Biology 3 (4): 392–9. April 2001. doi:10.1038/35070076. PMID 11283613. 
  84. ↑ "An alternative pathway for gene regulation by Myc". The EMBO Journal 16 (18): 5672–86. September 1997. doi:10.1093/emboj/16.18.5672. PMID 9312026. 
  85. ↑ "PSICQUIC View". http://www.ebi.ac.uk/Tools/webservices/psicquic/view/results.xhtml?conversationContext=1. 

Further reading

External links



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