Phorbol ester-induced expression of airway squamous cell differentiation marker, SPRR1B, is regulated by protein kinase Cdelta /Ras/MEKK1/MKK1-dependent/AP-1 signal transduction pathway.

Vuong, H; Patterson, T; Shapiro, P; Kalvakolanu, D V; Wu, R; Ma, W Y; Dong, Z; Kleeberger, S R; Reddy, S P

Vuong, H; Patterson, T; Shapiro, P; Kalvakolanu, D V; Wu, R; Ma, W Y; Dong, Z; Kleeberger, S R; Reddy, S P.

Afiliación

Vuong H; Department of Environmental Health Sciences, The Johns Hopkins University School of Public Health, Baltimore, Maryland 21205, USA.

J Biol Chem ; 275(41): 32250-9, 2000 Oct 13.

Article en En | MEDLINE | ID: mdl-10918063

RESUMEN

The transcriptional induction of SPRR1B by phorbol 12-myristate 13-acetate (PMA) is mainly mediated by the first -152-base pair 5'-flanking region containing two functional AP-1 sites. In this study, we have analyzed the signaling pathways that mediate the induction in tracheobronchial epithelial cells. PKC inhibitor ablated PMA-stimulated expression of endogenous SPRR1B and reporter gene expression driven by SPRR1B promoter. PKC activator promoted the transcription. The dominant negative protein kinase Cdelta (dn-PKCdelta) and rottlerin (PKCdelta inhibitor) completely suppressed PMA-stimulated promoter activity. dn-Ras or dn-MEKK1 inhibited PMA-stimulated promoter activity, while their corresponding constitutively active mutants augmented it. dn-c-Raf-1 did not have any effect on reporter gene expression. Since MEKK1 activates multiple parallel pathways, we examined involvement of JNK/SAPK, p38, and MKK1 in promoter regulation. Co-expression of the dominant negative forms of MKK4, MKK7, JNK/SAPK, MKK3, MKK6, or p38alpha did not suppress PMA-stimulated reporter gene expression. However, MKK1 inhibitors UO126 and PD98095 suppressed gene expression. Consistent with this, expression of dn-MKK1 strongly suppressed PMA-stimulated promoter activity, while the constitutively active MKK1 augmented it. However, MKK1-mediated induction of SPRR1B probably does not depend on extracellular signal-regulated kinases 1 and 2, suggesting the requirement of another kinase(s). dn-c-Jun mutants abolished PMA-stimulated expression supporting an important role for AP-1 proteins in SPRR1B expression. Together, these results suggest that a PKCdelta/Ras/MEKK1/MKK1-dependent/AP-1 pathway regulates the PMA-inducible expression of the SPRR1B in tracheobronchial epithelial cells.

Asunto(s)

Regulación de la Expresión Génica/efectos de los fármacos; Isoenzimas/metabolismo; Quinasa 1 de Quinasa de Quinasa MAP; Sistema de Señalización de MAP Quinasas/efectos de los fármacos; Proteína Quinasa C/metabolismo; Proteínas/genética; Acetato de Tetradecanoilforbol/farmacología; Factor de Transcripción AP-1/metabolismo; Proteínas ras/metabolismo; Diferenciación Celular; Línea Celular; Proteínas Ricas en Prolina del Estrato Córneo; Células Epiteliales/citología; Células Epiteliales/efectos de los fármacos; Células Epiteliales/enzimología; Células Epiteliales/metabolismo; Genes Reporteros; Genes jun/genética; Humanos; Isoenzimas/antagonistas & inhibidores; MAP Quinasa Quinasa 1; Proteínas de la Membrana; Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores; Quinasas de Proteína Quinasa Activadas por Mitógenos/genética; Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo; Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores; Proteínas Quinasas Activadas por Mitógenos/genética; Proteínas Quinasas Activadas por Mitógenos/metabolismo; Modelos Biológicos; Mutación/genética; Regiones Promotoras Genéticas/genética; Proteína Quinasa C/antagonistas & inhibidores; Proteína Quinasa C-delta; Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores; Proteínas Serina-Treonina Quinasas/genética; Proteínas Serina-Treonina Quinasas/metabolismo; Proteínas/metabolismo; ARN Mensajero/genética; ARN Mensajero/metabolismo; Sistema Respiratorio/citología; Sistema Respiratorio/efectos de los fármacos; Sistema Respiratorio/enzimología; Sistema Respiratorio/metabolismo

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína Quinasa C / Acetato de Tetradecanoilforbol / Proteínas / Regulación de la Expresión Génica / Factor de Transcripción AP-1 / Proteínas ras / Sistema de Señalización de MAP Quinasas / Quinasa 1 de Quinasa de Quinasa MAP / Isoenzimas Tipo de estudio: Prognostic_studies Idioma: En Revista: J Biol Chem Año: 2000 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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