7-methylguanosine and Neoplasms

Eukaryotic initiation factor 4E (eIF4E), a fundamental effector and rate limiting element of protein synthesis, binds the 7-methylguanosine cap at the 5' end of eukaryotic messenger RNA (mRNA) specifically as a constituent of eIF4F translation initiation complex thus facilitating the recruitment of mRNA to the ribosomes. This review focusses on the engagement of signals contributing to growth factor originated maxim and their role in the activation of eIF4E to achieve a collective influence on cellular growth, with a key focus on conjuring vital processes like protein synthesis. The review invites considerable interest in elevating the appeal of eIF4E beyond its role in regulating translation viz a viz cancer genesis, attributed to its phosphorylation state that improves the prospect for the growth of the cancerous cell. This review highlights the latest studies that have envisioned to target these pathways and ultimately the translational machinery for therapeutic intervention. The review also brings forward the prospect of eIF4E to act as a converging juncture for signaling pathways like mTOR/PI3K and Mnk/MAPK to promote tumorigenesis.

Topics: Eukaryotic Initiation Factor-4E; Guanosine; Humans; Neoplasms; Phosphorylation; Protein Biosynthesis; Ribosomes; RNA Cap-Binding Proteins; RNA, Messenger; Signal Transduction

In eukaryotic cells, protein synthesis is a complex and multi-step process that has several mechanisms to start the translation including cap-dependent and cap-independent initiation. The translation control of eukaryotic gene expression occurs principally at the initiation step. In this context, it is critical that the eukaryotic translation initiation factor eIF4E bind to the 7-methylguanosine (m7G) cap present at the 5'-UTRs of most eukaryotic mRNAs. Combined with other initiation factors, eIF4E mediates the mRNA recruitment on ribosomes to start the translation. Moreover, the eIF4E nuclear bodies are involved in the export of specific mRNAs from the nucleus to the cytoplasm. In this review, we focus on the eIF4E structure and its physiological functions, and describe the role of eIF4E in cancer development and progression and the current therapeutic strategies to target eIF4E.

Topics: 5' Untranslated Regions; Cell Nucleus; Eukaryotic Initiation Factor-4E; Guanosine; Humans; Molecular Targeted Therapy; Neoplasms; Protein Biosynthesis; Ribosomes; RNA, Messenger; Structure-Activity Relationship

c-Myc is upregulated in response to growth factors and transmits the signal to proliferate by altering the gene expression landscape. When genetic alterations result in growth factor-independent c-Myc expression, it can become an oncogene. The majority of human tumour types exhibit a degree of c-Myc deregulation, resulting in unrestrained cell proliferation. c-Myc binds proximal to the promoter region of genes and recruits co-factors including histone acetyltransferases and RNA pol II kinases, which promote transcription. c-Myc also promotes formation of the cap structure at the 5' end of mRNA. The cap is 7-methylguanosine linked to the first transcribed nucleotide of RNA pol II transcripts via a 5' to 5' triphosphate bridge. The cap is added to the first transcribed nucleotide by the capping enzymes, RNGTT and RNMT-RAM. During the early stages of transcription, the capping enzymes are recruited to RNA pol II phosphorylated on Serine-5 of the C-terminal domain. The mRNA cap protects transcripts from degradation during transcription and recruits factors which promote RNA processing including, splicing, export and translation initiation. The proportion of transcripts with a cap structure is increased by elevating c-Myc expression, resulting in increased rates of translation. c-Myc promotes capping by promoting RNA pol II phosphorylation and by upregulating the enzyme SAHH which neutralises the inhibitory bi-product of methylation reactions, SAH. c-Myc-induced capping is required for c-Myc-dependent gene expression and cell proliferation. Targeting capping may represent a new therapeutic opportunity to inhibit c-Myc function in tumours. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology.

Topics: Cell Proliferation; Gene Expression Regulation, Neoplastic; Guanosine; Humans; Neoplasms; Protein Biosynthesis; Proto-Oncogene Proteins c-myc; RNA Polymerase II; RNA, Messenger

Spontaneous mutations seem to be caused almost entirely by endogenous lesions. The pattern of these lesions along a gene represents an equilibrium between damage and repair. A pattern can be measured using ligation-mediated PCR (polymerase chain reaction) and a large chronic dose of a suspected endogenous mutagen. A study using dimethylsulfate-induced 7meGuanine lesions indicates that the exogenously induced pattern depends on how methyl purine glycosylase recognizes sequence context and, for this lesion, the pattern may be independent of the mutagen's dose.

Topics: DNA Adducts; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Guanosine; Humans; Male; Models, Genetic; Molecular Epidemiology; Mutagenesis; Mutagens; Mutation; Neoplasms; Sulfuric Acid Esters