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Bioorganic Chemistry(Chemistry)

Shimojo MasahitoSpecially Appointed Assosiate Professor

The transcriptional repressor REST (NRSF) controls the expression of genes in the nervous system, which is important factor in the program of neurogenesis and is involved in various diseases. Abnormal REST expression is closely related to the onset of diseases such as neurological diseases and cancer, we thus aim to research and develop unprecedented therapeutic agents by controlling REST gene expression. Nucleic acid therapeutics are attracting attention because they can specifically control the expression of several disease-related genes, unlike conventional medicine.

Research theme

Study of antisense oligonucleotide medicine for the treatment of refractory neuroendocrine cancer

Small cell lung cancer (SCLC) is the most malignant tumor of lung cancer has a high mortaility rate. We identified SRRM4 (Ser/Arg repetitive matrix 4) that is abnormally highly expressed in SCLC and induces tumor formation and growth. We thus started to study the development of antisense oligonucleotide medicine targeting SRRM4. We are developing SRRM4 targeted antisense nucleic acid medicine for SCLC and treatment-resistant prostate cancer/breast cancer.
"Small cell lung cancer therapeutic agent containing oligonucleotide" (PCT / JP2019 / 030090)

Study of transcriptional repressor REST splice-switching oligonucleotide

We are conducting research on oligonucleotides that control the pre-mRNA splicing of the transcriptional repressor REST for therapeutic medicine for intractable diseases (small cell lung cancer, heart failure, etc.) that are thought to be caused by abnormal splicing of the REST gene. "Oligonucleotide inducing N-exon skipping in processing of REST pre-mRNA" (PCT / JP2022 / 8079)

Study of non-coding microRNA (miR-4516) in patients as a companion diagnostic for personalized medicine

We are conducting research toward the realization of personalized medicine by discovering specific miRNAs involved in SRRM4 expression in the blood of SCLC patients and using them as companion diagnostics for cancer. We are aiming to realize personalized medicine that combines SRRM4 targeted antisense nucleic acid therapeutic agents and minimally invasive companion diagnostics that analyze blood miRNAs that stratify patients.
Diagnostic and therapeutic agents for small cell lung cancer Patent 6467580 (January 25, 2019)

Representative achievements

Shimojo M, Kasahara Y, Inoue M, Tsunoda SI, Shudo Y, Kurata T, Obika S. Sci. Rep. 9(1) 7618-7618, 2019.
A gapmer antisense oligonucleotide targeting SRRM4 is a novel therapeutic medicine for lung cancer.

Shimojo M, Shudo Y, Ikeda M, Kobashi T, Ito S.
Mol. Cancer Res. 11(10) 1258-1268, 2013.
The small cell lung cancer-specific isoform of RE1-silencing transcription factor (REST) is regulated by neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100).

Shimojo M.
Genes Cells 16(1) 90-100, 2011.
RE1-silencing transcription factor (REST) and REST-interacting LIM domain protein (RILP) affect P19CL6 differentiation.

Shimojo M.
J. Biol. Chem. 283(50) 34880-34886, 2008.
Huntingtin Regulates RE1-silencing Transcription Factor/Neuron-restrictive Silencer Factor (REST/NRSF) Nuclear Trafficking Indirectly through a Complex with REST/NRSF-interacting LIM Domain Protein (RILP) and Dynactin p150(Glued).

Bassuk AG, Wallace RH, Buhr A, Buller AR, Afawi Z, Shimojo M, Miyata S, Chen S, Gonzalez-Alegre P, Griesbach HL, Wu S, Nashelsky M, Vladar EK, Antic D, Ferguson PJ, Cirak S, Voit T, Scott MP, Axelrod JD, Gurnett C, Daoud AS, Kivity S, Neufeld MY, Mazarib A, Straussberg R, Walid S, Korczyn AD, Slusarski DC, Berkovic SF, El-Shanti HI.
Am. J. Hum. Genet. 83(5) 572-581, 2008.
A Homozygous Mutation in Human PRICKLE1 Causes an Autosomal-Recessive Progressive Myoclonus Epilepsy-Ataxia Syndrome.

Shimojo M, Hersh LB.
J. Neurochem. 96(4) 1130-1138, 2006.
Characterization of the REST/NRSF-interacting LIM domain protein (RILP): localization and interaction with REST/NRSF

Shimojo M, Hersh LB.
Mol. Cell. Biol. 23(24) 9025-9031, 2003.
REST/NRSF-interacting LIM domain protein, a putative nuclear translocation receptor

Shimojo M, Lee JH, Hersh LB.
J. Biol. Chem. 276(16) 13121-13126, 2001.
Role of zinc finger domains of the transcription factor neuron-restrictive silencer factor/repressor element-1 silencing transcription factor in DNA binding and nuclear localization

Shimojo M, Paquette AJ, Anderson DJ, Hersh LB.
Mol. Cell. Biol. 19(10) 6788-6795, 1999.
Protein kinase A regulates cholinergic gene expression in PC12 cells: REST4 silences the silencing activity of neuron-restrictive silencer factor/REST.

Shimojo M, Wu DH, Hersh LB.
J. Neurochem. 71(3) 1118-1126, 1998.
The cholinergic gene locus is coordinately regulated by protein kinase A II in PC12 cells.