title: Transforming growth factor-beta-activated kinase 1 is essential for differentiation and the prevention of apoptosis in epidermis.
abstract: Transforming growth factor-beta-activated kinase 1 (TAK1) is a member of the mitogen-activated protein (MAP) kinase family and is an upstream signaling molecule of nuclear factor-kappaB (NF-kappaB). Given that NF-kappaB regulates keratinocyte differentiation and apoptosis, TAK1 may be essential for epidermal functions. To test this, we generated keratinocyte-specific TAK1-deficient mice from Map3k7(flox/flox) mice and K5-Cre mice. The keratinocyte-specific TAK1-deficient mice were macroscopically indistinguishable from their littermates until postnatal day 2 or 3, when the skin started to roughen and wrinkle. This phenotype progressed, and the mice died by postnatal day 7. Histological analysis showed thickening of the epidermis with foci of keratinocyte apoptosis and intra-epidermal micro-abscesses. Immunohistochemical analysis showed that the suprabasal keratinocytes of the TAK1-deficient epidermis expressed keratin 5 and keratin 14, which are normally confined to the basal layer. The expression of keratin 1, keratin 10, and loricrin, which are markers for the suprabasal and late phase differentiation of the epidermis, was absent from the TAK1-deficient epidermis. Furthermore, the TAK1-deficient epidermis expressed keratin 16 and had an increased number of Ki67-positive cells. These data indicate that TAK1 deficiency in keratinocytes results in abnormal differentiation, increased proliferation, and apoptosis in the epidermis. However, the keratinocytes from the TAK1-deficient epidermis induced keratin 1 in suspension culture, indicating that the TAK1-deficient keratinocytes retain the ability to differentiate. Moreover, the removal of TAK1 from cultured keratinocytes of Map3k7(flox/flox) mice resulted in apoptosis, indicating that TAK1 is essential for preventing apoptosis. In conclusion, TAK1 is essential in the regulation of keratinocyte growth, differentiation, and apoptosis.
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295. Electronic address: sayama@m.ehime-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Sayama
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hanakawa
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagai
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirakata
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
authors.forename: Xiuju
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirakawa
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
authors.forename: Sho
authors.initials: S
authors.lastname: Tokumaru
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Tohyama
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
authors.forename: Lujun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Research Institute for Microbial Disease, Osaka University, Suita 565-0871, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.affiliation: Research Institute for Microbial Disease, Osaka University, Suita 565-0871, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shizuo
authors.affiliation: Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
authors.forename: Koji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology; D015603:Keratinocytes / Q000201:enzymology; D007633:Keratins / Q000032:analysis; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D007633:Keratins; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7