Abstract
Extensive efforts have been made to understand the molecular actors that control epithelial cell fate. Although pieces of information have been obtained from single-gene function investigations, the entire picture of the molecular mechanisms involved in the regulation of epithelial homeostasis is still mysterious. Growing data indicate that gene networks rather than single “master” genes dictate cell fate. In an attempt to characterize such gene networks, we have been investigating the human keratinocyte proliferation and differentiation genes that act downstream of the transcription factor p63, a major regulator of epidermal homeostasis. We identified two networks: the cell cycle network that controls cell proliferation and the keratinocyte cell fate network. Through further analysis of the existing data on epithelial tumorigenesis and induced pluripotent stem cells, we propose a wind rose model of cell fate that is based on a balance between these two different networks that ultimately control human keratinocyte fate and epidermal homeostasis.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-014-1758-1) contains supplementary material, which is available to authorized users.
Highlights
Extensive efforts have been made to understand the molecular actors that control epithelial cell fate
Pieces of information have been obtained from single-gene function investigations, the entire picture of the molecular mechanisms involved in the regulation of epithelial homeostasis is still mysterious
Through further analysis of the existing data on epithelial tumorigenesis and induced pluripotent stem cells, we propose a wind rose model of cell fate that is based on a balance
Summary
The human skin is our outermost layer that protects us against physical, chemical, and biological assaults from the external environment. In 2006 we undertook a ChIP-on-chip screening approach using the human keratinocyte cell line HaCaT, which predominantly expresses the DNp63a isoform, a truncated N amino terminal isoform that lacks the transactivating domain of p63 and were the first to identify 186 highconfidence p63 targets, which were validated using different biological assays [15]. We reanalyzed these data with less stringent criteria, extended the list of targets to over 1,000, and confirmed the pivotal role of p63 in transcriptional regulation [16]. Our result observed both in the HaCaT cell line (mutated p53) and in normal human primary keratinocytes (wild-type p53) demonstrated that cell cycle arrest in p63-depleted keratinocyte could be p53-independent and MYC-dependent [21]
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