p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity.
p53 homologue, p51/p63, predominantly expressed in keratinocyte stem cells, is indispensable for the formation of epidermis. Notch1, another such gene indispensable for the process, induces growth arrest and differentiation in keratinocytes. We found that exogenous expression of DeltaNp51B (DeltaNp63alpha), one of the isoforms of p51 specifically expressed in basal keratinocytes, blocked Notch 1-dependent growth arrest and differentiation in mouse keratinocytes by inhibiting p21 expression and maintaining integrins expression. Furthermore, DeltaNp51B by itself was found to have ability to induce expression of integrin alpha6beta4, which promotes attachment of basal cells to basal membrane thereby keeping the cells in immature state. Therefore, we conclude that DeltaNp51B expression warrants integrin expression even under the influence of Notch1 and that DeltaNp51B is a long-sought factor required to maintain basal cell keratinocytes immaturity by inhibiting Notch1 activity. We will postulate a plausible model explaining the maintenance of the squamous epithelium architectures as well as offering mechanistic explanations for pathological features of skin diseases, including cancers, psoriasis along with physiological wound healings.
Okuyama
R
R
Department of Dermatology, Tohoku University, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Japan.
Ogawa
E
E
Nagoshi
H
H
Yabuki
M
M
Kurihara
A
A
Terui
T
T
Aiba
S
S
Obinata
M
M
Tagami
H
H
Ikawa
S
S
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016158:Genes, p53; D015603:Keratinocytes / Q000502:physiology*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics*; D020033:Protein Isoforms / Q000502:physiology; D051881:Receptor, Notch1 / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection
C497761:NOTCH1 protein, human; D010750:Phosphoproteins; D020033:Protein Isoforms; D051881:Receptor, Notch1; D015534:Trans-Activators; C486419:Trp63 protein, mouse