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

Hue Vuong, Tricia Patterson, Paul Shapiro, Dhananjaya V. Kalvakolanu, Reen Wu, Wei Ya Ma, Zigang Dong, Steven R. Kleeberger, Sekhar P M Reddy

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

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 Cδ (dn-PKCδ) and rottlerin (PKCδ 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 p38α 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 PKCδ/Ras/MEKK1/MKK1-dependent/AP-1 pathway regulates the PMA-inducible expression of the SPRR1B in tracheobronchial epithelial cells.

Original languageEnglish (US)
Pages (from-to)32250-32259
Number of pages10
JournalJournal of Biological Chemistry
Volume275
Issue number41
StatePublished - Oct 13 2000

ASJC Scopus subject areas

  • Biochemistry

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    Vuong, H., Patterson, T., Shapiro, P., Kalvakolanu, D. V., Wu, R., Ma, W. Y., Dong, Z., Kleeberger, S. R., & Reddy, S. P. M. (2000). Phorbol ester-induced expression of airway squamous cell differentiation marker, SPRR1B, is regulated by protein kinase Cδ/Ras/MEKK1/MKK1-dependent/AP-1 signal transduction pathway. Journal of Biological Chemistry, 275(41), 32250-32259.