Akio Yamashita Lab at the University of the Ryukyus

The basic biological science will benefit to investigate novel strategy of medicine. We are fortunate to be able to have a fan of science.  Hopefully, you will be with us to enjoy in revealing the post-transcriptional gene expression event.

Recruitment: Research Fellowship for Young Scientist: Application 2022.4~2022.6.2 17:00

Research

Human gene expression is exquisitely regulated at several points of between transcription and protein synthesis to ensure fidelity in the conversion of genetic information into biological functions. Nonsense-mediated mRNA decay (NMD) is a post-transcriptional surveillance pathway responsible for the recognition and degradation of mRNAs containing premature termination codons. NMD protects cells from nonfunctional, potentially harmful, polypeptides encoded by mutated mRNAs. On the other hand, NMD degrade frameshift or miss-spliced mRNAs encoding cancer antigen. Hence, manipulation of NMD activity will benefit to improve anti-cancer immune response. We are challenging this fundamental post-transcriptional gene expression regulation pathway and developing novel drugs for cancer and rear genetic diseases. Using our original technique, which developed during basic analysis of NMD, we are analyzing disease related post-transcriptional event of gene expression mechanisms. The goal of the research is to find the critical factors of diseases and develop/perform the primary compound screening targeting these factors.

Investigation of regulation mechanisms of mRNA surveillance
SMG-1, a member of the PIKK (phosphoinositide 3-kinase related kinases) family, plays a critical role in the mRNA quality control system known as nonsense-mediated mRNA decay (NMD). NMD protects the cells from the accumulation of aberrant mRNAs with premature termination codons (PTCs) that encode nonfunctional or potentially harmful truncated proteins. SMG-1 directly phosphorylates Upf1 helicase, another key component of NMD, and this phosphorylation occurs upon recognition of PTC on post-spliced mRNA during the initial round of translation. Phosphorylated-Upf1 recruits the SMG-5:SMG-7 complex to phospho-S1096 to induce ribosome dissociation and induce decapping mediated PTC-mRNA decay. Phospho-Upf1 also recruits SMG-6 endonuclease to phospho-T28 which might be involved in PTC-mRNA end-cleavage. Upf1 ATPase/helicase activity are likely required for the activation of mRNA decay enzymes and mRNP dissociation to complete NMD. We are investigating the physiological regulation mechanisms of NMD.
Development of new drugs targeting for nonsense-mRNA and post-transcriptional mRNA regulation
RNA plays a significant role in regulating a diverse set of biological processes and diseases. Recent progresses of the research of RNA regulation in combination with new technology unveil biological processes of various diseases. We focuses this process and technique regarding the relation of inflammations, viral infections, genetic diseases and cancer progressions to investigate new drug screening platform.
Analysis of post-transcriptional gene expression regulation for diverse biological processes and diseases
Eukaryotic gene expression is precisely regulated at all points between transcription and translation. In this review, we focus on translational control mediated by the 3'-untranslated regions (UTRs) of mRNAs. mRNA 3'-UTRs contain cis-acting elements that function in the regulation of protein translation or mRNA decay. Each RNA binding protein that binds to these cis-acting elements regulates mRNA translation via various mechanisms targeting the mRNA cap structure, the eukaryotic initiation factor 4E (eIF4E)-eIF4G complex, ribosomes, and the poly (A) tail. We are challenging this new frontier of the RNA based biology by combining biochemistry, molecular biology, and cellular biology and mice.