HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: fj.07-9080comv1 22/4/1155    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sato-Jin, K. Articles by Imokawa, G. PubMed PubMed Citation Articles by Sato-Jin, K. Articles by Imokawa, G.

Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders

Kayo Sato-Jin^*,1, Emi K. Nishimura^,,1, Eijiro Akasaka^*, Wade Huber, Hajime Nakano^*, Arlo Miller, Jinyan Du, Min Wu, Katsumi Hanada^*, Daisuke Sawamura^*, David E. Fisher and Genji Imokawa^*,,2

^* Department of Dermatology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan;

Department of Stem Cell Medicine, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan;

Dana-Farber Cancer Institute Melanoma Program and Children’s Hospital Boston, Department of Pediatric Hematology/Oncology, Harvard Medical School, Boston, Massachusetts, USA; and

Tokyo University of Technology, School of Bionics, Hachioji, Tokyo, Japan

²Correspondence: Tokyo University of Technology, School of Bionics, Katayanagi Institute-W204, 1404-1 Katakura Hachioji, Tokyo 192-0982 Japan. E-mail: imokawag{at}dream.ocn.ne.jp

Waardenburg syndrome (WS) is an inherited sensorineural deafness condition in humans caused by melanocyte deficiencies in the inner ear and forelock. Mutation of microphthalmia-associated transcription factor (MITF) is known to produce WS type IIA whereas mutations of either endothelin (EDN) or its receptor endothelin receptor B (EDNRB) produce WS type IV. However, a link between MITF haploinsufficiency and EDN signaling has not yet been established. Here we demonstrate mechanistic connections between EDN and MITF and their functional importance in melanocytes. Addition of EDN to cultured human melanocytes stimulated the phosphorylation of MITF in an EDNRB-dependent manner, which was completely abolished by mitogen-activated protein kinase kinase inhibition. The expression of melanocyte-specific MITF mRNA transcripts was markedly augmented after incubation with EDN1 and was followed by increased expression of MITF protein. Up-regulated expression of MITF was found to be mediated via both the mitogen-activated protein kinase-p90 ribosomal S6 kinase-cAMP response element-binding protein (CREB) and cAMP-protein kinase A-CREB pathways. In addition, EDNRB expression itself was seen to be dependent on MITF. The functional importance of these connections is illustrated by the ability of EDN to stimulate expression of melanocytic pigmentation and proliferation markers in an MITF-dependent fashion. Collectively these data provide mechanistic and epistatic links between MITF and EDN/EDNRB, critical melanocytic survival factors and WS genes.—Sato-Jin, K., Nishimura, E. K., Akasaka, E., Huber, W., Nakano, H., Miller, A., Du, J., Wu, M., Hanada, K., Sawamura, D., Fisher, D. E., Imokawa, G. Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders.

Key Words: cAMP response element-binding protein • CREB • cyclin-dependent kinase 2 • melanocyte • endothelin B receptor