Contact

Location: STRF 2.289.2

Department

Molecular Medicine

Masahiro Morita, PhD

Assistant Professor

Education

Year Degree Discipline Institution
2003 BS Chemistry and Biotechnology University of Tokyo
Tokyo , Japan
2005 MS Biophysics and Biochemistry University of Tokyo
Tokyo , Japan
2008 PhD Biochemistry and Biophysics University of Tokyo
Tokyo , Japan
Postdoctoral Training Medical Sciences University of Tokyo
Tokyo , Japan
Postdoctoral Training Cancer Metabolism McGill University
Montreal, Quebec, Canada

Research

Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells change their metabolic programs to efficiently utilize the limited nutrients, ultimately driving macromolecule synthesis (e.g., protein, lipid and nucleotide synthesis) and cell growth and proliferation. Protein, the most abundant macromolecule in the cell, is aberrantly synthesized in malignant cells. Post-transcriptional regulation of gene expression, including mRNA translation and degradation, directly modulate protein synthesis, and are dysregulated in a variety of metabolic diseases including cancer. However, the mechanisms that underpin the role of post-transcriptional regulation in controlling cancer and metabolism remain largely unknown. The focus on our research is to determine how mutually dependent changes in protein synthesis and cellular metabolism contribute to the development of cancer and metabolic diseases. To this end, we will investigate the role of one of the central energy-sensing signaling pathways known to regulate both cellular energetics and protein synthesis: the mammalian/mechanistic target of rapamycin (mTOR) pathway in cancer and metabolic diseases.

The mTOR complex 1 (mTORC1) pathway is one of the major oncogenic signaling pathways that stimulates anabolism (e.g., protein synthesis) and suppresses catabolism (e.g., autophagy) in response to nutrient availability through multiple downstream effectors (in the Figure below). Prominent ones include translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and ribosomal protein S6 kinases (S6Ks). 4E-BPs are translation initiation repressors, which bind to the mRNA 5’cap-binding protein eIF4E and prevent the assembly of the eIF4F complex, consisting of eIF4E, that facilitates ribosome recruitment to the mRNA. Phosphorylation of 4E-BPs by mTORC1 results in their dissociation from eIF4E, thus allowing assembly of the eIF4F complex and promoting protein synthesis and cell proliferation. The oncogenic activity of the mTORC1 pathway is mediated through 4E-BP-dependent translational activation of mRNAs encoding tumor-promoting proteins, such as cell cycle regulators and metabolic enzymes.

Our laboratory focuses on mTORC1-depenedent control of mRNA translation and degradation in cancer and metabolic diseases. We have developed a genome-wide analyses of mRNA translation and degradation to find the target mRNAs. Our genome-wide analysis reveals that the oncogenic mTORC1 signaling pathway stimulates not only global protein synthesis, but also translation of a subset of mRNAs that encode pivotal regulators of mitochondrial dynamics. Our group demonstrates that mTORC1 coordinates energy consumption by translation machinery, and energy production by bolstering mitochondrial functions and dynamics via regulation of 4E-BPs. Furthermore, we show that the CCR4-NOT poly(A) nuclease (deadenylase) controls susceptibility to metabolic disorders, which is a cancer-predisposing state, by selectively regulating turnover of mRNAs encoding hormone-like proteins. Dissecting the mechanistic underpinnings of these translational and metabolic signatures should provide a molecular basis to improve the efficacy of existing drugs and devise more effective therapies to treat poor outcome cancer patients. Taken together, our laboratory is currently highlighting the pathways that relate the post-transcriptional regulation to metabolic perturbations in cancer, which in long term will provide novel therapeutic avenues to target cancer energetics.