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Am. J. Respir. Cell Mol. Biol., Volume 27, Number 1, July, 2002 64-70

BMK1 (ERK5) Regulates Squamous Differentiation Marker SPRR1B Transcription in Clara-like H441 Cells

Sekhar P. M. Reddy, Pavan Adiseshaiah, Paul Shapiro, and Hue Vuong

Department of Environmental Health Sciences, Bloomberg School of Public Health, Baltimore; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore; and University of Maryland School of Pharmacy, Baltimore, Maryland

Various toxicants and carcinogens upregulate the expression of small proline-rich protein 1B (SPRR1B), a squamous differentiation marker, in bronchial epithelial cells both in vivo and in vitro. We have recently shown that phorbol 13-myristate 12-acetate (PMA)-stimulated SPRR1B transcription in Clara-like H441 cells is mainly mediated by activator protein-1 (AP-1) and c-Jun N-terminal kinase-1 (JNK1). Though mitogen-activated protein kinase (MAPK) kinase (MEK)-1/2 pathway inhibitors strongly suppressed both basal and PMA-inducible SPRR1B transcription, overexpression of dominant negative (dn) forms of extracellular signal-regulated kinase (ERK)-1 and/or -2 did not have any significant effect indicating the involvement of another ERK-like MAPK in this pathway. Here, we report for the first time the involvement of ERK5 in PMA-inducible SPRR1B transcription in H441 cells. PMA significantly induced ERK5 activation in H441 cells. Overexpression of dn-ERK5 strongly suppressed both basal and PMA-inducible SPRR1B transcription, whereas wild-type ERK5 upregulated it. Consistent with this, a mutant form of MEK-5, an upstream activator of ERK5, strongly suppressed PMA-inducible promoter activity. However, coexpression of c-Jun restored promoter activation suppressed by dn-ERK5. Thus, in addition to JNK1, the activation of MEK5-ERK5 MAPK pathway probably plays a pivotal role in transcriptional regulation of AP-1-mediated SPRR1B expression in the distal bronchiolar region.

Abbreviations: activator protein-1, AP-1; dimethyl sulfoxide, DMSO; dominant negative, dn; c-Jun N-terminal kinase-1, JNK-1; extracellular signal-regulated kinase, ERK; mitogen-activated protein kinase, MAPK; MAPK kinase, MEK; phorbol 13-myristate 12-acetate, PMA; small proline-rich protein 1B, SPRR1B.




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Copyright © 2002 American Thoracic Society.