Myc regulates keratinocyte adhesion and differentiation via complex formation with Miz1.
Myc plays a key role in homeostasis of the skin. We show that Miz1, which mediates Myc repression of gene expression, is expressed in the epidermal basal layer. A large percentage of genes regulated by the Myc-Miz1 complex in keratinocytes encode proteins involved in cell adhesion, and some, including the alpha6 and beta1 integrins, are directly bound by Myc and Miz1 in vivo. Using a Myc mutant deficient in Miz1 binding (MycV394D), we show that Miz1 is required for the effects of Myc on keratinocyte responsiveness to TGF-beta. Myc, but not MycV394D, decreases keratinocyte adhesion and spreading. In reconstituted epidermis, Myc induces differentiation and loss of cell polarization in a Miz1-dependent manner. In vivo, overexpression of beta1 integrins restores basal layer polarity and prevents Myc-induced premature differentiation. Our data show that regulation of cell adhesion is a major function of the Myc-Miz1 complex and suggest that it may contribute to Myc-induced exit from the epidermal stem cell compartment.
Gebhardt
Anneli
A
Institute for Cell Biology, University of Marburg, 35033 Marburg, Germany.
Frye
Michaela
M
Herold
Steffi
S
Benitah
Salvador Aznar
SA
Braun
Kristin
K
Samans
Birgit
B
Watt
Fiona M
FM
Elsässer
Hans-Peter
HP
Eilers
Martin
M
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology; D016259:Genes, myc / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics; D015603:Keratinocytes / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases
D019012:Integrin beta1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D016271:Proto-Oncogene Proteins c-myc; D016212:Transforming Growth Factor beta; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases