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Diabetes 54:2859-2866, 2005
© 2005 by the American Diabetes Association, Inc.

BETA2/NeuroD Protein Can Be Transduced Into Cells Due to an Arginine- and Lysine-Rich Sequence

Hirofumi Noguchi1,2, Susan Bonner-Weir2, Fan-Yan Wei3, Masayuki Matsushita3, and Shinichi Matsumoto4

1 Department of Transplantation and Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
2 Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
3 Department of Physiology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
4 Transplantation Unit, Kyoto University Hospital, Kyoto, Japan

BETA2/NeuroD, a basic helix-loop-helix transcription factor, is a key regulator of pancreatic islet morphogenesis and insulin gene transcription. Here we report for the first time that the BETA2/NeuroD protein can permeate several cells, including pancreatic islets, due to an arginine- and lysine-rich protein transduction domain sequence in its structure. The BETA2/NeuroD protein was transduced in a dose-dependent manner up to 1 µmol/l. Transduced BETA2/NeuroD functions similarly to endogenous BETA2/NeuroD: it binds to the insulin promoter and activates its expression. We also investigated the mechanism of BETA2/NeuroD protein transduction. The BETA2/NeuroD protein penetrated cells by macropinocytosis and was released from endosomes homogeneously in cytoplasm and nuclei. These data suggest that BETA2/NeuroD protein transduction could be a safe and valuable strategy for enhancing insulin gene transcription without requiring gene transfer technology.

Address correspondence and reprint requests to Hirofumi Noguchi, MD, PhD, Dept. of Transplantation and Immunology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: noguchih{at}kuhp.kyoto-u.ac.jp

Abbreviations: bHLH, basic helix-loop-helix; dNeuroD, deletion BETA2/NeuroD; dNeuroD-6, PTD-deleted BETA2/NeuroD protein; DsRed, Discosoma sp. red fluorescent protein; DynDN, dominant-negative mutant of dynamin-1; EGFP, enhanced green fluorescent protein; EGFP-PTD, EGFP with BETA2/NeuroD PTD; FITC, fluorescein isothiocyanate; PDX-1, pancreatic duodenal homeobox 1; PTD, protein transduction domain; TBST, Tris-buffered saline with Tween


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[Abstract] [Full Text] [PDF]


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Copyright © 2005 by the American Diabetes Association.