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C-MYC Signaling Pathway


Figure 1.C-MYC signaling pathway.

C-MYC overview

  1. MYC family protein

    The MYC-family of cellular proto-oncogenes encode three highly related nuclear phosphoprotein, C-MYC, N-MYC and L-MYC. The genes corresponding to these three proteins are located on chromosome 8, chromosome 2 and chromosome 1, respectively. The structure of MYC includes the first exon that does not encode a protein, and the other is the third exon that encodes a protein. The MYC gene belongs to an oncogene encoding a nuclear protein that encodes a nuclear DNA binding protein involved in cell cycle regulation. The MYC gene family and its products promote cell proliferation, immortalization, dedifferentiation and transformation.

  2. C-MYC structure and function

    The structure of C-MYC

    Figure 2. The structure of C-MYC

    The product of the C-MYC gene is the 62KD phosphorylated protein p62c-myc, which is located in the nucleus and is a nuclear protein consisting of 439 amino acids encoded by exons a and 3 of the c-myc gene. The C-MYC protein can be structurally divided into a transcriptional activation region, a non-specific DNA binding region, a nuclear target sequence, a basic region, a helix-loop-helix (HLH) and a leucine zipper region, among known transcription factors. It can mediate the oligomerization of proteins. The simultaneous presence of these two regions is unique to C-MYC protein. Among other proteins, it is rarely found. In C-MYC protein, the helix-ring-helix follows the alkaline the region reveals its interaction with DNA in a specific sequence. Studies in prokaryotes have shown that the basic region exists as a free loop and becomes a helix when bound to DNA in a special way. This region is the binding site of C-MYC protein to DNA specific sequence. The native protein C-MYC is a bHLHLZ (basic region/helix-loop-helix/leucine zipper) transcription factor that combines with a specific electronic box to form consistent core sequence 5’-CACGTG-3’.

C-MYC signaling pathway

In regulation cell growth and proliferation, the C-MYC protooncogene is depicted as a downsteam transduction pathway for receptor signaling that can cause positive or negative regulatory genes in C-MYC. The transcription factor C-MYC by C-MYC dimerizes with MAX and binds to the target DNA sequence or E-BOX (sequence 5’-CANNTG-3’) to regulate transcriptional proliferation of genes involved in cell growth and apoptosis. The negative regulation of APC describes the WNT pathway b-catenin, which is involved in transactivation of C-MYC deletions during nuclear translocation such that loss of APC leads to constitutive carcinogenic C-MYC expression. When C-MYC is deregulated, acute sustained oncogenic C-MYC expression leads to activation of p53 or Arf checkpoints by gene amplification, loss of chromosomal translocations or upstream modulators (eg, APC). Moreover, the heterodimeric MYC-Max can also mediate transcription and gene suppression, and the heterodimeric MYC-Max interacts with key cofactors, such as transcription factor 2H (TFIIH) triggers transcriptional elongation or recruiting transcription/transcriptional domain correlation. Protein (TRRAP) GCN5, an acetylated histone that allows transcription of a target gene. MYC-Max also mediates gene suppression by regulating the transcription of target genes through the Miz-1 line together promoter (INR) element, which may be a silent C-MYC replacement nuclear phosphoprotein (NPM), a Miz-1 cofactor, or C-MYC induces the ribosomal protein RPL23, which retains the NPM nucleolus, away from Miz-1.C-MYC also regulates miRNA networks, and C-MYC regulates miRNA network by stimulating miR-17-92 to occlude and suppress dozens of miRs, including recent Let-7, which affects insulin signaling, miR-23a/b, and glutaminase Expression and miR-34a, which is shown to regulate lactate dehydrogenase (LDHA) expression. The miR-17 cluster contains miRNAs that target PTEN, thereby activating AKT, as well as those that target pro-apoptotic BimL or transcription factor E2F1. miRNAs downstream of C-MYC are also associated with EMT and angiogenesis.

Relationship with tumor

C-MYC is one of the most frequently mutated genes in tumors. Since the overexpression of C-MYC is the cause of complete tumorigenesis, the interference with C-MYC expression is effective in tumor therapy, and C-MYC becomes a very attractive target for anticancer treatment. Deregulation of C-MYC has been found in most human tumors. In most cases, the rapid release of C-MYC is unregulated, but mutations in the C-MYC are rare. This enhanced or constitutive C-MYC expression can be the result of mutations in the C-MYC locus or in the signal transduction pathway that regulates C-MYC expression. Since C-MYC induces apoptosis in a normal cell without a sufficient amount of survival factor, activation of the oncogene C-MYC strongly selects a second mutation that abolishes the apoptotic pathway (eg, p53) or is used for activation. Two synergistic oncogenes. Inhibits apoptosis and stimulates cell survival (eg, Bcl-2, Bcl-xL, Ras). However, if C-MYC induces apoptosis inhibition (for example, by co-expression of the anti-apoptotic protein bcl-xl and bcl2, or due to an excess of local survival factors), C-MYC activation itself is sufficient to cause cells in no other conditions cancerous. Vice versa, activation of the oncogene C-MYC alone can induce persistent tumor regression, reverse and abolish tumorigenesis, and lead to complete permanent loss of tumor phenotype, a result that is a significant advance to the tumor treatment process. It also reminds us that C-MYC can be a key breakthrough point in cancer treatment.

References

  1. Hutter Sonja, Bolin Sara, Weishaupt Holger, et al. Modeling and Targeting MYC Genes in Childhood Brain Tumors. Genes (Basel), 2017, 8(4).
  2. Ji Xiaoyu, Wang Yucheng, Liu Guifeng. Expression analysis of MYC genes from Tamarix hispida in response to different abiotic stresses. [J]. Int J Mol Sci, 2012, 13(2): 1300-13.
  3. Marandel Lucie, Labbe Catherine, Bobe Julien, et al. Evolutionary history of c-myc in teleosts and characterization of the duplicated c-myca genes in goldfish embryos. [J]. Mol. Reprod. Dev, 2012, 79(2): 85-96.
  4. Wierstra Inken, Alves Jürgen. The c-myc promoter: still MysterY and challenge. [J]. Adv. Cancer Res, 2008, 99: 113-333.
  5. Dang Chi V. MYC on the path to cancer. [J]. Cell, 2012, 149(1): 22-35.

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