Myc

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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, l-myc, and n-myc. 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]

In the human genome, C-myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes[4] through binding on enhancer box sequences (E-boxes).[5]

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.[6]

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 (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 an oncogene is its implication in Burkitt lymphoma. In Burkitt 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 c-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 elongation factors.[7] 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.[8]

Myc is activated upon various mitogenic signals such as serum stimulation or by Wnt, Shh and EGF (via the MAPK/ERK pathway).[9] 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,[10] which are necessary for Myc induced proliferation[11] or cell growth.[12]

There have been several studies that have clearly indicated Myc's role in cell competition.[13]

A major effect of c-myc is B cell proliferation.[14]

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.[15] 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.

Myc-Nick

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.[16]

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.[17]

Amplification of the MYC gene was found in a significant number of epithelial ovarian cancer cases.[18] In TCGA datasets, the amplification of Myc occurs in several cancer types, including breast, colorectal, pancreatic, gastric, and uterine cancers.[19]

In the experimental transformation process of normal cells into cancer cells, the MYC gene can cooperate with the RAS gene.[20][21]

Expression of Myc is highly dependent on BRD4 function in some cancers.[22][23] BET inhibitors have been used to successfully block Myc function in pre-clinical cancer models and are currently being evaluated in clinical trials.[24][25]

Animal models

In Drosophila Myc is encoded by the diminutive locus, (which was known to geneticists prior to 1935).[26] Calssical diminutive alleles resulted in a viable animal with small body size. Drosophila has subsequently been used to implicate Myc in cell competition,[27] endoreplication,[28] and cell growth.[29]

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. 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.[30][31]

Relationship to Stem Cells

c-Myc plays a major role in the generation of induced pluripotent stem cells (iPSCs). It 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 with:

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

See also

References

  1. ↑ 1.0 1.1 "Myc". NCBI.
  2. ↑ Finver SN, Nishikura K, Finger LR, Haluska FG, Finan J, Nowell PC, Croce CM (May 1988). "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. doi:10.1073/pnas.85.9.3052. PMC 280141. PMID 2834731.
  3. ↑ Begley S (2013-01-09). "DNA pioneer James Watson takes aim at cancer establishments". Reuters.
  4. ↑ Gearhart J, Pashos EE, Prasad MK (October 2007). "Pluripotency redux--advances in stem-cell research". The New England Journal of Medicine. 357 (15): 1469–72. doi:10.1056/NEJMp078126. PMID 17928593.
  5. ↑ Denis N, Kitzis A, Kruh J, Dautry F, Corcos D (August 1991). "Stimulation of methotrexate resistance and dihydrofolate reductase gene amplification by c-myc". Oncogene. 6 (8): 1453–7. PMID 1886715.
  6. ↑ Cotterman R, Jin VX, Krig SR, Lemen JM, Wey A, Farnham PJ, Knoepfler PS (December 2008). "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. doi:10.1158/0008-5472.CAN-08-1961. PMC 2637654. PMID 19047142.
  7. ↑ Rahl PB, Young RA (January 2014). "MYC and transcription elongation". Cold Spring Harbor Perspectives in Medicine. 4 (1): a020990. doi:10.1101/cshperspect.a020990. PMC 3869279. PMID 24384817.
  8. ↑ Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, Galloway DA, Gu W, Gautier J, Dalla-Favera R (July 2007). "Non-transcriptional control of DNA replication by c-Myc". Nature. 448 (7152): 445–51. doi:10.1038/nature05953. PMID 17597761.
  9. ↑ Campisi J, Gray HE, Pardee AB, Dean M, Sonenshein GE (1984). "Cell-cycle control of c-myc but not c-ras expression is lost following chemical transformation". Cell. 36 (2): 241–7. doi:10.1016/0092-8674(84)90217-4. PMID 6692471.
  10. ↑ Liu YC, Li F, Handler J, Huang CR, Xiang Y, Neretti N, Sedivy JM, Zeller KI, Dang CV (July 2008). "Global regulation of nucleotide biosynthetic genes by c-Myc". PLOS One. 3 (7): e2722. doi:10.1371/journal.pone.0002722. PMC 2444028. PMID 18628958.
  11. ↑ Mannava S, Grachtchouk V, Wheeler LJ, Im M, Zhuang D, Slavina EG, Mathews CK, Shewach DS, Nikiforov MA (August 2008). "Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells". Cell Cycle. 7 (15): 2392–400. doi:10.4161/cc.6390. PMC 3744895. PMID 18677108.
  12. ↑ Aughey GN, Grice SJ, Liu JL (February 2016). "The Interplay between Myc and CTP Synthase in Drosophila". PLoS Genetics. 12 (2): e1005867. doi:10.1371/journal.pgen.1005867. PMC 4759343. PMID 26889675.
  13. ↑ Clavería C, Giovinazzo G, Sierra R, Torres M (August 2013). "Myc-driven endogenous cell competition in the early mammalian embryo". Nature. 500 (7460): 39–44. doi:10.1038/nature12389. PMID 23842495.
  14. ↑ de Alboran IM, O'Hagan RC, Gärtner F, Malynn B, Davidson L, Rickert R, Rajewsky K, DePinho RA, Alt FW (January 2001). "Analysis of C-MYC function in normal cells via conditional gene-targeted mutation". Immunity. 14 (1): 45–55. doi:10.1016/S1074-7613(01)00088-7. PMID 11163229.
  15. ↑ Conacci-Sorrell M, Ngouenet C, Eisenman RN (August 2010). "Myc-nick: a cytoplasmic cleavage product of Myc that promotes alpha-tubulin acetylation and cell differentiation". Cell. 142 (3): 480–93. doi:10.1016/j.cell.2010.06.037. PMC 2923036. PMID 20691906.
  16. ↑ Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, Wang R, Green DR, Tessarollo L, Casellas R, Zhao K, Levens D (September 2012). "c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells". Cell. 151 (1): 68–79. doi:10.1016/j.cell.2012.08.033. PMC 3471363. PMID 23021216.
  17. ↑ Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, Skinner SO, Xu Q, Li MZ, Hartman ZC, Rao M, Yu P, Dominguez-Vidana R, Liang AC, Solimini NL, Bernardi RJ, Yu B, Hsu T, Golding I, Luo J, Osborne CK, Creighton CJ, Hilsenbeck SG, Schiff R, Shaw CA, Elledge SJ, Westbrook TF (January 2012). "A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis". Science. 335 (6066): 348–53. doi:10.1126/science.1212728. PMC 4059214. PMID 22157079.
  18. ↑ Ross JS, Ali SM, Wang K, Palmer G, Yelensky R, Lipson D, Miller VA, Zajchowski D, Shawver LK, Stephens PJ (September 2013). "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. doi:10.1016/j.ygyno.2013.06.019. PMID 23791828.
  19. ↑ Chen Y, McGee J, Chen X, Doman TN, Gong X, Zhang Y, Hamm N, Ma X, Higgs RE, Bhagwat SV, Buchanan S, Peng SB, Staschke KA, Yadav V, Yue Y, Kouros-Mehr H (2014). "Identification of druggable cancer driver genes amplified across TCGA datasets". PLOS One. 9 (5): e98293. doi:10.1371/journal.pone.0098293. PMC 4038530. PMID 24874471.
  20. ↑ Land H, Parada LF, Weinberg RA (1983). "Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes". Nature. 304 (5927): 596–602. doi:10.1038/304596a0. PMID 6308472.
  21. ↑ Radner H, el-Shabrawi Y, Eibl RH, Brüstle O, Kenner L, Kleihues P, Wiestler OD (1993). "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. doi:10.1007/bf00228580. PMID 8310796.
  22. ↑ Fowler T, Ghatak P, Price DH, Conaway R, Conaway J, Chiang CM, Bradner JE, Shilatifard A, Roy AL (2014). "Regulation of MYC expression and differential JQ1 sensitivity in cancer cells". PLOS One. 9 (1): e87003. doi:10.1371/journal.pone.0087003. PMC 3900694. PMID 24466310.
  23. ↑ Shi J, Vakoc CR (June 2014). "The mechanisms behind the therapeutic activity of BET bromodomain inhibition". Molecular Cell. 54 (5): 728–36. doi:10.1016/j.molcel.2014.05.016. PMC 4236231. PMID 24905006.
  24. ↑ Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS (September 2011). "BET bromodomain inhibition as a therapeutic strategy to target c-Myc". Cell. 146 (6): 904–17. doi:10.1016/j.cell.2011.08.017. PMC 3187920. PMID 21889194.
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  28. ↑ Maines JZ, Stevens LM, Tong X, Stein D (February 2004). "Drosophila dMyc is required for ovary cell growth and endoreplication". Development. 131 (4): 775–86. doi:10.1242/dev.00932. PMID 14724122.
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  33. ↑ 33.0 33.1 Li H, Lee TH, Avraham H (June 2002). "A novel tricomplex of BRCA1, Nmi, and c-Myc inhibits c-Myc-induced human telomerase reverse transcriptase gene (hTERT) promoter activity in breast cancer". The Journal of Biological Chemistry. 277 (23): 20965–73. doi:10.1074/jbc.M112231200. PMID 11916966.
  34. ↑ Xiong J, Fan S, Meng Q, Schramm L, Wang C, Bouzahza B, Zhou J, Zafonte B, Goldberg ID, Haddad BR, Pestell RG, Rosen EM (December 2003). "BRCA1 inhibition of telomerase activity in cultured cells". Molecular and Cellular Biology. 23 (23): 8668–90. doi:10.1128/mcb.23.23.8668-8690.2003. PMC 262673. PMID 14612409.
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  54. ↑ 54.0 54.1 Mac Partlin M, Homer E, Robinson H, McCormick CJ, Crouch DH, Durant ST, Matheson EC, Hall AG, Gillespie DA, Brown R (February 2003). "Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX". Oncogene. 22 (6): 819–25. doi:10.1038/sj.onc.1206252. PMID 12584560.
  55. ↑ Blackwood EM, Eisenman RN (March 1991). "Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc". Science. 251 (4998): 1211–7. doi:10.1126/science.2006410. PMID 2006410.
  56. ↑ Lee CM, Onésime D, Reddy CD, Dhanasekaran N, Reddy EP (October 2002). "JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors". Proceedings of the National Academy of Sciences of the United States of America. 99 (22): 14189–94. doi:10.1073/pnas.232310199. PMC 137859. PMID 12391307.
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  59. ↑ Meroni G, Reymond A, Alcalay M, Borsani G, Tanigami A, Tonlorenzi R, Lo Nigro C, Messali S, Zollo M, Ledbetter DH, Brent R, Ballabio A, Carrozzo R (May 1997). "Rox, a novel bHLHZip protein expressed in quiescent cells that heterodimerizes with Max, binds a non-canonical E box and acts as a transcriptional repressor". The EMBO Journal. 16 (10): 2892–906. doi:10.1093/emboj/16.10.2892. PMC 1169897. PMID 9184233.
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