Rescue of key features of the p63-null epithelial phenotype by inactivation of Ink4a and Arf.
Mice lacking p63 cannot form skin, exhibit craniofacial and skeletal defects, and die soon after birth. The p63 gene regulates a complex network of target genes, and disruption of p63 has been shown to affect the maintenance of epithelial stem cells, the differentiation of keratinocytes, and the preservation of the adhesive properties of stratified epithelium. Here, we show that inactivation of p63 in mice is accompanied by aberrantly increased expression of the Ink4a and Arf tumour suppressor genes. In turn, anomalies of the p63-null mouse affecting the skin and skeleton are partially ameliorated in mice lacking either Ink4a or Arf. Rescue of epithelialization is accompanied by restoration of keratinocyte proliferative capacity both in vivo and in vitro and by expression of markers of squamous differentiation. Thus, in the absence of p63, abnormal upregulation of Ink4a and Arf is incompatible with skin development.
Su
Xiaohua
X
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cho
Min Soon
MS
Gi
Young-Jin
YJ
Ayanga
Bernard A
BA
Sherr
Charles J
CJ
Flores
Elsa R
ER
D020727:ADP-Ribosylation Factors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D012867:Skin / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D020727:ADP-Ribosylation Factors