title: BMK1 (ERK5) regulates squamous differentiation marker SPRR1B transcription in Clara-like H441 cells.
abstract: 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.
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. sreddy@jhsph.edu
authors.forename: Sekhar P M
authors.initials: SP
authors.lastname: Reddy
authors.forename: Pavan
authors.initials: P
authors.lastname: Adiseshaiah
authors.forename: Paul
authors.initials: P
authors.lastname: Shapiro
authors.forename: Hue
authors.initials: H
authors.lastname: Vuong
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D055233:Cornified Envelope Proline-Rich Proteins; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
chemical_list: D055233:Cornified Envelope Proline-Rich Proteins; D008565:Membrane Proteins; D011506:Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C524533:SPRR1B protein, human; D019908:Proto-Oncogene Proteins c-raf; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate