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A Specific Epitope of Protein Inhibitor of Activated STAT3 Is Responsible for the Induction of Apoptosis in Rat Transformed Mast Cells¹

Zohar Yagil^*, Gillian Kay^*, Hovav Nechushtan^2, and Ehud Razin^2,*

^* Department of Biochemistry, Hebrew University Hadassah Medical School, Jerusalem, Israel; and Oncology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Protein inhibitor of activated STAT3 (PIAS3) functions in vivo as a key molecule in suppressing the transcriptional activity of both microphthalmia transcription factor (MITF) and STAT3, two transcription factors that play a major role in the development, phenotypic expression, and survival of mast cells and melanocytes. In the present study we have investigated the role played by PIAS3 in the regulation of cell cycle in mast cells and melanocytes. We have characterized the biological role of a 23-aa domain derived from PIAS3 that induces apoptosis in these cells by inhibiting the transcriptional activity of both MITF and STAT3. This PIAS3 inhibitor peptide could serve as the beginning of an in depth study for the development of peptide inhibitors for MITF and STAT3.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the U.S.-Israel Binational Science Foundation (Grant 2003–009), the Israeli Academy of Science (Grant 144/04), the German-Israel Foundation for Scientific Research and Development (Grant I-726–10.2), and the Israel Cancer Association (all to E.R.).

Z.Y. designed and performed the research; collected, analyzed, and interpreted data; and wrote the manuscript. H.N. designed the research, interpreted, data and wrote the manuscript. G.K. interpreted data and wrote the manuscript. E.R., designed the research, interpreted the data, and wrote the manuscript.

² Address correspondence and reprint requests to: Dr. Ehud Razin, Department of Biochemistry, or Dr. Hovav Nechushtan, Oncology Department, Hebrew University Hadassah Medical School, P.O. Box 12272, Jerusalem, Israel. E-mail addresses: ehudr{at}ekmd.huji.ac.il or hovavnech{at}hadassah.org.il

³ Abbreviations used in this paper: MITF, microphthalmia transcription factor; BMMC, bone marrow-derived mast cells; mMCP, mouse mast cell protease; PIAS3, protein inhibitor of activated STAT3; RBL, rat basophilic leukemia; siRNA, small interfering RNA.