Smads mediate signaling of the TGFβ superfamily in normal keratinocytes but are lost during skin chemical carcinogenesis

Abstract

The Smads are the signaling mediators of the TGFb superfamily. In the present study, we examined Smad expression in mouse epidermis and chemically-induced skin tumors. Mutations in Smad2 and -4 genes were also screened. Transcripts of Smad1 through -5 were constantly expressed in the epidermis regardless of changes in TGFb signaling, state of dierentiation and stages of carcinogenesis. Smad7 transcripts were barely detectable in keratinocytes, but were induced by TGFb1 treatment and in chemically-induced skin tumors. At the protein level, Smad1 was detected throughout the epidermis, whereas Smad2 through -5 exhibited greater levels in suprabasal layers than basal keratinocytes. In cultured keratinocytes, Smad2, -3 and -4 underwent nuclear translocation upon TGFb1 treatment. Furthermore, nuclear translocation of Smads correlated with decreased BrdU labeling in proliferative keratinocytes. Although no mutations were detected in the Smad2 and -4 genes in tumors, proteins of Smad1 through -5 were partially or completely lost in carcinomas. These data document that Smads are expressed at high levels in the epidermis and mediate signaling of the TGFb superfamily. During skin carcinogenesis, loss of Smad1 through -5 and overexpression of Smad7 may contribute to the loss of growth inhibition mediated by TGFb superfamily members, thus resulting in tumor progression. Oncogene (2001) 20, 471 ± 483.

Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin

“…Our data indicated that Smad1-5 were expressed in all layers of the epidermis, including both the basal proliferative keratinocytes and suprabasal differentiated keratinocytes, whereas Smad6 and 7 were barely detectable in the epidermis (He et al, 2001). In the hair follicle, expression of Smad2 and 3 was quite weak, while Smad1, 4 and 5 were detected with intensities similar to those in the epidermis.…”

“…It is known Smad4 interacts with Smad1, 5 and 8 to mediate BMP signaling, and with Smad2 and 3 to mediate signaling of TGFb subfamily members, while BMPR1A only mediates signals of BMP subfamily (Heldin et al, 1997;Massague, 1998;ten Dijke and Hill, 2004). We have shown previously that all these Smads, except for Smad8, whose expression in skin has not been studied, are expressed in hair follicles and epidermis (He et al, 2001). Thus, it is plausible that the increased cell proliferation in the epidermis and ORS of the hair follicle is largely due to a block of signals of the TGFb subfamily.…”

Smad3 Knockout Mice Exhibit a Resistance to Skin Chemical Carcinogenesis

“…In vitro studies have shown that TGF-␤-induced growth inhibition in epithelial cells is preferentially mediated by Smad3 (10,11) and that cyclin-dependent kinase (cdk) 2 and cdk4 can phosphorylate Smad3, thus inactivating its ability to instigate cell cycle arrest (12). Therefore, Smad3 may mediate TGF-␤1-induced growth inhibition during cancer development.…”

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

“…12,17,18 Furthermore, in chemically induced murine epidermal tumors and in human basal cell carcinoma cells, Smad1/5 are strongly down-regulated. 19 Skin-specific disruption of Smad4 results in increased epidermal proliferation consequently leading to squamous cell carcinoma formation. 20,21 Antitumor activity of BMPs may also be regulated by extracellular BMP inhibitors: expression of the BMP antagonist gremlin increased in basal cell carcinomas, in which gremlin promotes and BMPs inhibit cell proliferation.…”