Ovol1 regulates the growth arrest of embryonic epidermal progenitor cells and represses c-myc transcription

Abstract

Transcriptional control plays a key role in regulating epidermal proliferation and differentiation. Although ample information has been obtained on how epidermal homeostasis is controlled in adult skin, less is known about the control of proliferation/differentiation of epidermal stem/progenitor cells in the developing embryo. Ovol1, encoding a zinc finger protein homologous to Drosophila melanogaster Ovo, is expressed in embryonic epidermal progenitor cells that are transiting from proliferation to terminal differentiation. In this study, we demonstrate a function for Ovol1 in interfollicular epidermal development. In its absence, developing epidermis fails to properly restrict the proliferative potential of progenitor cells, and cultured keratinocytes fail to efficiently undergo growth arrest in response to extrinsic growth-inhibitory signals. We present molecular evidence that c-myc expression is up-regulated in Ovol1-deficient suprabasal cells and that Ovol1 represses c-myc transcription by directly binding to its promoter. Collectively, our findings indicate that Ovol1 is required for proliferation exit of committed epidermal progenitor cells and identify c-myc as an Ovol1 target.

The tumor suppressor activity of IKKα in stratified epithelia is exerted in part via the TGF-β antiproliferative pathway

“…Interestingly, and as found by analysis of Ikk␣ Ϫ/Ϫ epidermis (14), our expression analysis showed marked down-regulation of Ovol1, Max dimerization protein 1 (Mad1, Mxd1), and Mxi1 (Mad2), known as TGF-␤-induced inhibitors of c-Myc transcription and activity (21)(22)(23), but not of Ovol2, Mad3, and Mad4, suggesting that the hyperproliferation observed in Ikk␣-deficient keratinocytes ( Fig. 3 and ref.…”

“…2B), thus confirming the gene profiling results. Mad1 and Ovol1 are upregulated in nuclei of suprabasal keratinocytes, and their expression correlates spatially and temporally with exit of keratinocytes from the cell cycle and expression of differentiation markers (22,24). Mad1 and IKK␣ had similar expression patterns in human skin because they were both expressed in the nuclei of suprabasal layers (Fig.…”

“…Specifically, IKK␣ is required for expression of 2 negative regulators of c-Myc transcription and activity, Mad1 and Ovol1, both of which regulate cell cycle exit keratinocyte differentiation (22,27). Mad1 is a direct binding partner of the Max protein, thereby disrupting Myc:Max oligomers and contributing to down-regulation of c-Myc transcriptional activity, whereas Ovol1 represses c-Myc expression through association with its promoter (22,28). As suggested by ChIP experiments, IKK␣ may serve as a direct coactivator of Ovol1 and Mad1 transcription as it is recruited to their promoters upon TGF-␤ stimulation.…”

Ovol2 Suppresses Cell Cycling and Terminal Differentiation of Keratinocytes by Directly Repressing c-Myc and Notch1

“…For instance, Ovol1 is activated by the ␤-catenin-LEF1 complex, downstream effectors of Wnt signaling (13), and is a downstream target of TGF-␤/BMP7-Smad4 signaling (14,15). A functional Ovol1 gene is required for multiple developmental processes, including that of epidermis, hair follicles, kidney, and male germ cell differentiation (2,4,10). In both epidermis and testis, Ovol1 restricts the boundary of late progenitor cells during development by promoting cell cycle exit (2,4).…”

“…Ovo proteins contain four DNA-binding C 2 H 2 zinc fingers at the C termini and possess transcriptional regulatory activities (1)(2)(3)(4)(5). Drosophila ovo, the founding member of the family, acts genetically downstream of Wg (fly Wnt homolog) and DER (fly epidermal growth factor receptor homolog) signaling pathways and is required for epidermal denticle formation and oogenesis (6 -8).…”