Identification of receptors and Smad proteins involved in activin signalling in a human epidermal keratinocyte cell line

Shimizu, Akira; Kato, Mitsuyasu; Nakao, Akihiro; Imamura, Takeshi; Dijke, Peter ten; Heldin, Carl‐Henrik; Kawabata, Masahiro; Shimada, Shinji; Miyazono, Kohei

doi:10.1046/j.1365-2443.1998.00174.x

Cited by 68 publications

(51 citation statements)

References 59 publications

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“…This was confirmed by our recent results, which demonstrated that activin receptor signaling in keratinocytes is important for hair follicle morphogenesis and wound re-epithelialization (Bamberger et al, 2005). In addition, a role of activin in the regulation of keratinocyte proliferation and differentiation was found in in vitro studies with keratinocyte monocultures, where a weak inhibitory effect of activin on keratinocyte proliferation and induction of keratinocyte differentiation by this factor was demonstrated (Shimizu et al, 1998;Seishima et al, 1999). In addition, activin was shown to stimulate keratinocyte migration (Zhang et al, 2005).…”

supporting

confidence: 78%

“…Similar to TGF-b, activin has opposite effects on keratinocytes and fibroblasts. It slightly reduces keratinocyte proliferation (Shimizu et al, 1998;Seishima et al, 1999), but enhances growth of cultured fibroblasts (Ohga et al, 1996;Yamashita et al, 2004). The different responses of fibroblasts and keratinocytes to activin and TGF-b are reflected by the opposite regulation of Id expression in both cell types, suggesting that the up-or downregulation of Id proteins by activin/TGF-b could mediate -at least in part -the effects of these factors on proliferation of fibroblasts and keratinocytes.…”

Section: Id Proteins In Epidermal Homeostasismentioning

confidence: 99%

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Id proteins: Novel targets of activin action, which regulate epidermal homeostasis

et al. 2005

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Activin is a member of the transforming growth factor b (TGF-b) family, which plays a crucial role in skin morphogenesis and wound healing. To gain insight into the underlying mechanisms of action, we searched for activin-regulated genes in cultured keratinocytes. One of the identified target genes encodes Id1, a negative regulator of helix-loop-helix transcription factors. We show that Id1, Id2, and Id3 are strongly downregulated by activin in keratinocytes in vitro and in vivo. To determine the role of Id1 in keratinocyte biology, we generated stable HaCaT keratinocyte cell lines overexpressing this protein. Our results revealed that enhanced levels of Id1 do not affect proliferation of keratinocytes in monoculture under exponential culture conditions or in response to activin or TGF-b1. However, in three-dimensional organotypic cultures, Id1-overexpressing HaCaT cells formed a hyperthickened and disorganized epithelium that was characterized by enhanced keratinocyte proliferation, abnormal differentiation, and an increased rate of apoptosis. These results identify an important function of Id1 in the regulation of epidermal homeostasis.

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confidence: 78%

Section: Id Proteins In Epidermal Homeostasismentioning

confidence: 99%

Id proteins: Novel targets of activin action, which regulate epidermal homeostasis

et al. 2005

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“…Recent studies from us and from others have revealed a novel role of the TGF-b superfamily member activin in the regulation of keratinocyte proliferation and di erentiation (Shimizu et al, 1998;Seishima et al, 1999;Munz et al, 1999). Interestingly, the e ects of activin on keratinocytes seem to di er from those of Figure 7 Expression of mxi1/mad2, mad3, mad4, mnt/rox, c-myc and mmip1 mRNAs in normal and wounded skin.…”

Section: Discussionmentioning

confidence: 98%

“…A picture of the RNA gel is shown below the RNase protection assays. The same set of RNAs was used for the RNase protection assays shown here and in Figure 5 TGF-b, since the latter caused a much stronger inhibition of keratinocyte proliferation in vitro compared to activin (Shimizu et al, 1998;Seishima et al, 1999). In vivo, the di erences were even more striking, since targeted expression of TGF-b1 in the epidermis of transgenic mice caused severe inhibition of keratinocyte proliferation (Sellheyer et al, 1993, Wang et al, 1999.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, transgenic mice that overexpress the activin bA chain in the basal layer of the epidermis revealed ®brosis in the dermis and a hyperthickened epidermis which was characterized by abnormal keratinocyte di erentiation (Munz et al, 1999). A role of activin in the regulation of keratinocyte proliferation and di erentiation was further supported by in vitro studies demonstrating a weak inhibitory e ect of activin on keratinocyte proliferation and induction of keratinocyte di erentiation by this factor (Shimizu et al, 1998;Seishima et al, 1999). Besides this obvious function of activin in normal skin, recent studies from our laboratory demonstrated a novel and important role of activin in wound repair.…”

Section: Introductionmentioning

confidence: 92%

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The Mad1 transcription factor is a novel target of activin and TGF-β action in keratinocytes: possible role of Mad1 in wound repair and psoriasis

et al. 2001

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Activin A, a member of the transforming growth factor beta (TGF-b) superfamily, a ects keratinocyte proliferation and di erentiation in vitro and in vivo. However, little is known about the mechanisms of activin action in keratinocytes, and its target genes have not been identi®ed. In this study, we demonstrate that activin A and TGF-b1 directly induce the expression and activity of Mad1, an antagonist of the c-Myc transcription factor, in the human HaCaT keratinocyte cell line. Expression and activity of Mad1 was strongly induced by both factors in keratinocytes, although the intensity of induction was di erent for activin A and TGF-b1. To determine a possible role of activin and TGF-b in the regulation of mad1 expression in vivo, we analysed its expression during cutaneous wound repair when high levels of these factors are present. Expression of mad1 mRNA and protein, but not of other mad genes, increased signi®cantly after skin injury, particularly in polymorphonuclear leukocytes and in suprabasal keratinocytes of the hyperproliferative epithelium. Elevated levels of mad1 mRNA were also detected in the hyperthickened epidermis of psoriatic patients. Since Mad1 regulates proliferation and/or di erentiation of various cell types, our results suggest that this transcription factor mediates at least in the part the anti-mitotic and/or di erentiation-inducing activities of TGF-b and activin in keratinocytes. Oncogene (2001) 20, 7494 ± 7504.

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Role of p38 mitogen-activated protein kinases in ultraviolet-B irradiation-induced activator protein 1 activation in human keratinocytes

Chen

Bowden

2000

Mol. Carcinog.

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The effects of p38 mitogen‐activated protein kinases on ultraviolet (UV) B irradiation–induced activator protein 1 (AP‐1) activation were studied in a human keratinocyte cell line, HaCaT. The HaCaT cells were stably transfected with a plasmid containing a promoter fragment of human collagenase 1 driving a luciferase reporter gene. There is an AP‐1–binding site within this fragment, without any other known transcription factor–binding sites. As we reported previously, UVB significantly induces activation of AP‐1 and p38 in HaCaT cells. SB202190, a p38‐specific inhibitor, inhibits UVB‐induced p38 activation and c‐fos gene expression. In the present study, we further examined the role of p38 in UVB‐induced AP‐1 activation. We observed that SB202190 strongly inhibited UVB‐induced AP‐1 transactivation at different time points and UVB doses in transfected HaCaT cells. Furthermore, SB202190 markedly inhibited UVB‐induced AP‐1 DNA binding as determined by mobility shift analyses. These results suggested, for the first time, that activation of p38 is required for UVB‐induced AP‐1 activation in human keratinocytes. In addition, a potential mechanism of UVB‐induced AP‐1 activation through p38 is to enhance AP‐1 complex binding to its target DNA. Because c‐fos gene expression plays a critical role in UVB‐induced AP‐1 activation and p38 is required for UVB‐induced c‐fos gene expression in HaCaT cells, as reported previously, a potential UVB signaling cascade for AP‐1 activation in human keratinocytes has been determined. This cascade involves UVB, p38 activation, c‐fos gene expression, and AP‐1 activation. Mol. Carcinog. 28:196–202, 2000. © 2000 Wiley‐Liss, Inc.

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Identification of receptors and Smad proteins involved in activin signalling in a human epidermal keratinocyte cell line

Cited by 68 publications

References 59 publications

Id proteins: Novel targets of activin action, which regulate epidermal homeostasis

Id proteins: Novel targets of activin action, which regulate epidermal homeostasis

The Mad1 transcription factor is a novel target of activin and TGF-β action in keratinocytes: possible role of Mad1 in wound repair and psoriasis

Role of p38 mitogen-activated protein kinases in ultraviolet-B irradiation-induced activator protein 1 activation in human keratinocytes

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