As components of E3 ubiquitin ligase complexes, Siah proteins facilitate ubiquitination and degradation of diverse protein targets and are involved in many biological processes such as apoptosis, hypoxia response, cell cycle control, proliferation and migration. However, the potential role of these proteins in cell differentiation in defined skin epithelial compartments remains unknown. 
To address this issue we assessed patterns of Siah1 expression in human skin (epidermis and hair follicles) and primary human keratinocytes (hPKC) using immunofluorescence, immunocytochemistry and qRT-PCR. Given that the most pronounced hypoxia is associated with the upper (most differentiated) keratinocyte layers of the epidermis, we also assessed Siah1 expression levels under hypoxia conditions. 
In hPKC, the expression of differentiation markers (K1, K10, INV and FLG) as well as Siah1 was significantly upregulated by both the Ca2+switch (after 24h and 48h) and hypoxia (3, 6, 18 and 24h exposure to 1%O2). In the hPKC, cultured under low Ca2+ (0.1 mM ), Siah1 expression was low and localization was primary nuclear. After treatment with 1.5 mM Ca2+, an increase of cytoplasmic Siah1 levels was observed. A similar increase in cytoplasmic Siah1 protein levels was observed in response to hypoxia (1%O2 8h, 24h). 
IF revealed that Siah1 is localized primarily in the suprabasal layers of the human epidermis and is co-localized with the differentiation marker K10. Nevertheless, Siah1 was also detected in a few cells of the basal layer (cytoplasmic), suggesting that it may also be associated with control of cell proliferation. In the hair follicle, Siah1 was detected during anagen and catagen stages primarily in the ORS and IRS regions and in some parts of the hair matrix. These results, as well as changes of Siah1 expression in vitro after Ca2+ and hypoxia treatment, are suggestive of Siah1 implication in control of keratinocyte differentiation.

Siah1 expression is associated with keratinocyte differentiation in the epidermis and the hair follicle