Transforming growth factor-beta-activated kinase 1 is essential for differentiation and the prevention of apoptosis in epidermis.
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.
Sayama
Koji
K
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295. Electronic address: sayama@m.ehime-u.ac.jp.
Hanakawa
Yasushi
Y
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
Nagai
Hiroshi
H
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
Shirakata
Yuji
Y
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
Dai
Xiuju
X
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
Hirakawa
Satoshi
S
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
Tokumaru
Sho
S
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
Tohyama
Mikiko
M
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
Yang
Lujun
L
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
Sato
Shintaro
S
Research Institute for Microbial Disease, Osaka University, Suita 565-0871, Japan.
Shizuo
Akira
A
Research Institute for Microbial Disease, Osaka University, Suita 565-0871, Japan.
Hashimoto
Koji
K
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
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
D007633:Keratins; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7