Epistatic connections between microphthalmia‐associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders
| Autor: | Min Wu, Kayo Sato-Jin, Jinyan Du, David E. Fisher, Hajime Nakano, Daisuke Sawamura, Wade E. Huber, Katsumi Hanada, Genji Imokawa, Emi K. Nishimura, Eijiro Akasaka, Arlo J. Miller |
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| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Melanocyte CREB medicine.disease_cause Biochemistry Internal medicine otorhinolaryngologic diseases Genetics medicine Humans Waardenburg Syndrome Inner ear Phosphorylation Cyclic AMP Response Element-Binding Protein Molecular Biology Microphthalmia-Associated Transcription Factor Mutation Mitogen-Activated Protein Kinase 3 biology Waardenburg syndrome Endothelins Epistasis Genetic medicine.disease Microphthalmia-associated transcription factor eye diseases medicine.anatomical_structure Endocrinology biology.protein Melanocytes sense organs Endothelin receptor CREB1 Pigmentation Disorders Signal Transduction Biotechnology |
| Zdroj: | The FASEB Journal. 22:1155-1168 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.07-9080com |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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