The unfolded protein response is activated in differentiating epidermal keratinocytes

J Invest Dermatol. 2009 Sep;129(9):2126-35. doi: 10.1038/jid.2009.51. Epub 2009 Mar 12.


The unfolded protein response (UPR), which is induced by stress to the endoplasmic reticulum (ER), is involved in the functional alteration of certain cells, such as the differentiation of B cells to plasma cells. The aim of this study is to determine whether the UPR is activated during epidermal keratinocyte (KC) differentiation. Here, we show that the expression of the UPR-induced proteins Bip/GRP78 and HRD1 was increased in cells in the supra-basal layers of normal human epidermis that contain KCs undergoing differentiation as well as in skin-equivalent cultured KCs. However, Bip/GRP78 and HRD1 were poorly expressed in proliferating KCs in squamous cell carcinoma and psoriasis vulgaris tissues. The epidermal growth factor receptor tyrosine kinase inhibitor, PD153035, which induces KC differentiation, upregulated UPR-induced marker mRNAs and proteins. Furthermore, microarray analyses and quantitative PCR revealed that ER stress-inducing reagents, tunicamycin (TU), thapsigargin, and brefeldin A, altered the expression of genes essential for human epidermal KC differentiation, including C/EBPbeta, KLF4, and ABCA12 in vitro. However, ABCA12 and KLF4 mRNA did not increase with TU treatment after siRNA-mediated knockdown of XBP-1. Taken together, our findings strongly suggest that the UPR is activated during normal epidermal KC differentiation and induces C/EBPbeta, KLF4, and ABCA12 mRNAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • Carcinoma, Squamous Cell / chemistry
  • Cell Differentiation
  • DNA-Binding Proteins / genetics
  • Endoplasmic Reticulum / metabolism*
  • Heat-Shock Proteins / analysis
  • Heat-Shock Proteins / genetics
  • Humans
  • Immunohistochemistry
  • Keratinocytes / cytology
  • Keratinocytes / metabolism*
  • Kruppel-Like Transcription Factors / genetics
  • Middle Aged
  • Protein Disulfide-Isomerases / analysis
  • Protein Disulfide-Isomerases / genetics
  • Protein Folding*
  • Protein Transport
  • Psoriasis / metabolism
  • Quinazolines / pharmacology
  • RNA, Messenger / analysis
  • Regulatory Factor X Transcription Factors
  • Signal Transduction / physiology*
  • Transcription Factors / genetics
  • Ubiquitin-Protein Ligases / analysis
  • X-Box Binding Protein 1


  • ABCA12 protein, human
  • ATP-Binding Cassette Transporters
  • CCAAT-Enhancer-Binding Protein-beta
  • DNA-Binding Proteins
  • GKLF protein
  • Heat-Shock Proteins
  • Kruppel-Like Transcription Factors
  • Quinazolines
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • SYVN1 protein, human
  • Ubiquitin-Protein Ligases
  • Protein Disulfide-Isomerases
  • 4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline
  • molecular chaperone GRP78