The human MYC genes belong to the family of oncogenes andproto-oncogenes and play a significant role in the development of tumors 1-5 that causes deaths of 100,000 million peopleworldwide every year. These genes have threewell-characterized members; c-myc, N-myc, and L-myc genes, which code fornuclear DNA binding phosphoproteins. Indeed, several studies have demonstrated the rolein MYC gene in tumorigenesis, apoptosis, metastasis,and drug resistance 6,7. L-MYC and N-MYC were identified as amplified, myc homologous DNAsequences in cell lines from neuroblastoma (N-myc) 8,9 6,7 and human small cell lung carcinoma (L-myc)10. The L-myc and N-mycgenes have three-exons which havesimilarities with c-myc gene.
. The MYC genes are differentially regulated where c-myc isactive in almost all proliferating cell 11-15. L-myc is expressed in developing brain, kidney,spleen, thymus, pancreas, lung, and skin whereas N-myc has not expression inthese tissues 16-19.
Importantly, L-Myc expression is verylow in adult bone marrow and in fetal spleen and thymus. It is composed of three exons and two introns spanning inhuman DNA. In caseof, Acute Myelogenous Leukemia (AML), L-Myc process with a unique pattern that lack exon III and intron I 20. Different mRNA transcripts are generated in cell lunggrowth cell lines that express L-myc. These transcripts are produce withalternative splicing of introns 1 and 2 and by use of alternativepolyadenylation signals.
In afew mRNAs there is a long ORF with an anticipated deciphered protein of 364amino acids having reliable homology with the c-myc and N-myc. interestingly, other mRNAtranscripts, produced by elective processing, could encode a truncated proteinwith a novel carboxy-terminal end. However, thefunctional role splicing variants in leukemogenicity has not been defined yet. Two isoforms of Kit transcripts created through thealternate use of 5′ splice donor sites (alternative splicing) are detected inAML 21. But further analysis of these demonstrated no apparent associationwith pathology of AML 22. An alternatively spliced IL-6R mRNA, encoding soluble IL-6R (sIL-6R)expressed in 64% of the primary blast cells of AML patients which supports theevidence of alternative splicing as a mechanism of sIL-6R production in AML23. Precursor mRNA orpre-mRNA splicing is a critical step in regulation of post-transcriptionalgene expression that provides significant expansion of the functional proteome.Alternativesplicing and splicing are markedly affects by the mutations within thecis-acting elements.
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These elements are important for correct pre-mRNAprocessing. Alternative splicing markedly affects the human development and itsmisregulation underlies many human diseases and its misregulation can be more subtle contributions to thedeterminants of disease susceptibility 24. Itis believe that 94% of human genes are alternatively spliced and of which 50% of disease causing mutations affect thesplicing process which is carried out by the spliceosome that recognize certainconservative recognition sites within the exonic and intronic sequences.The variations and their effects in splice sites of L-MYC gene have notbeen deeply addressed. The past decade has seen numerous developments in the field of in silico splicing prediction and can be benefited from the newgeneration in silico research tools. There are several free or commerciallyavailable tools today that fulfill the various needs of the splicing process.
Therefore, for the first stepsthis study will utilize the use of an insilico system to analyze the various mutations affecting the splicingmechanism of L-MYC mRNA.
