title: BNIP3 plays crucial roles in the differentiation and maintenance of epidermal keratinocytes.
abstract: Transcriptome analysis of the epidermis of Hes1(-/-) mouse revealed the direct relationship between Hes1 (hairy and enhancer of split-1) and BNIP3 (BCL2 and adenovirus E1B 19-kDa-interacting protein 3), a potent inducer of autophagy. Keratinocyte differentiation is going along with activation of lysosomal enzymes and organelle clearance, expecting the contribution of autophagy in this process. We found that BNIP3 was expressed in the suprabasal layer of the epidermis, where autophagosome formation is normally observed. Forced expression of BNIP3 in human primary epidermal keratinocytes (HPEKs) resulted in autophagy induction and keratinocyte differentiation, whereas knockdown of BNIP3 had the opposite effect. Intriguingly, addition of an autophagy inhibitor significantly suppressed the BNIP3-stimulated differentiation of keratinocytes, suggesting that BNIP3 plays a crucial role in keratinocyte differentiation by inducing autophagy. Furthermore, the number of dead cells increased in the human epidermal equivalent of BNIP3 knockdown keratinocytes, which suggests that BNIP3 is important for maintenance of skin epidermis. Interestingly, although UVB irradiation stimulated BNIP3 expression and cleavage of caspase3, suppression of UVB-induced BNIP3 expression led to further increase in cleaved caspase3 levels. This suggests that BNIP3 has a protective effect against UVB-induced apoptosis in keratinocytes. Overall, our data provide valuable insights into the role of BNIP3 in the differentiation and maintenance of epidermal keratinocytes.
authors.affiliation: Pharmaceutical Research and Technology Institute, Kinki University, Higashi-Osaka, Osaka, Japan; Platform for Realization of Regenerative Medicine, Foundation for Biomedical Research and Innovation, Kobe, Hyogo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Moriyama
authors.affiliation: Pharmaceutical Research and Technology Institute, Kinki University, Higashi-Osaka, Osaka, Japan. Electronic address: mariko@phar.kindai.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Moriyama
authors.affiliation: Pharmaceutical Research and Technology Institute, Kinki University, Higashi-Osaka, Osaka, Japan.
authors.forename: Junki
authors.initials: J
authors.lastname: Uda
authors.affiliation: Platform for Realization of Regenerative Medicine, Foundation for Biomedical Research and Innovation, Kobe, Hyogo, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Matsuyama
authors.affiliation: Division of Regeneration Technology, Gifu University School of Medicine, Gifu, Gifu, Japan.
authors.forename: Masatake
authors.initials: M
authors.lastname: Osawa
authors.affiliation: Pharmaceutical Research and Technology Institute, Kinki University, Higashi-Osaka, Osaka, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Hayakawa
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D004817:Epidermis / Q000378:metabolism*; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D018398:Homeodomain Proteins / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D000072056:Transcription Factor HES-1; C090121:BNIP3 protein, human; C508686:BNip3 protein, mouse; C489734:Hes1 protein, mouse