Concerted action of TGF-beta 1 and its type II receptor in control of epidermal homeostasis in transgenic mice.

Abstract

Transforming growth factor-131 (TGF-I~I) is a modulator of cellular proliferation, differentiation, and extracellular matrix deposition. It is a potent epithelial growth inhibitor and can alter the differentiative properties of keratinocytes, in vitro, but little is known about its normal physiological function in the epidermis in vivo. Transgenic mice were generated using a keratin 10 (K10) gene promoter to drive constitutive expression of TGF-~I in the suprabasal keratinocyte compartment. Surprisingly, these mice showed a two-to threefold increase in epidermal DNA labeling index over control mice, in the absence of hyperplasia. The transgene, however, acted in the expected fashion, as a negative regulator of cell growth, when hyperplasia was induced by treatment by 12-tetradecanoyl-phorbol-13-acetate (TPA). Epidermal TGF-[~ type I and II receptor (T~RI and T[~RII) levels were examined in control and transgenic mice during induction of hyperplasia by TPA. Whereas T~RI levels remained relatively constant, T~RII expression was strongly induced in TPA-treated skins, prior to the induction of the growth inhibitory response to TGF-131, and its level of expression correlated with growth sensitivity to TGF-~I in vivo and in vitro. These results suggest that TGF-I$1 and its type II receptor are part of the endogenous homeostatic regulatory machinery of the epidermis.

Expression of a dominant negative type II TGF-β receptor in mouse skin results in an increase in carcinoma incidence and an acceleration of carcinoma development

“…In the longterm TPA promoted skin from our transgenic mice and from wild-type mice endogeneous mouse type II TGF-b receptor is still upregulated in the epidermis and in the outer root sheath of the hair follicle. In previous reports it has been described that the type II TGF-b receptor is induced by single TPA treatment, but the expression declined 36 h after treatment (Cui et al, 1995;Fowlis et al, 1996). Our result indicates that in longterm TPA treated skin TGF-b signaling through the type II receptor is still possible.…”

“…In one transgenic line weak expression was also seen in kidney. Northern blot analysis revealed a strong overexpression of the transgene speci®c transcript of 2.4 kb length as compared to the endogeneous TGF-b type II receptor transcript of 4.4 kb length (Cui et al, 1995;Knaus et al, 1996). Western blot analysis con®rmed that the transgene derived RNA which encodes a 286 aa polypeptide gives rise to a protein of 44 kDa.…”

“…By contrast, mice with a targeted deletion of the TGF-b1 gene showed hyperproliferation in the epidermis . In addition, TGF-b1 overexpression in the epidermis of transgenic mice may cause either an increase or a decrease of proliferation possibly depending on the pattern of transgene expression (Sellheyer et al, 1993;Cui et al, 1995). Some explanation for these seemingly contradictory results can be provided by the notion that inhibition and promotion of proliferation through the three di erent TGF-b isoforms, TGF-b1, -b2, -b3, is balanced and that there may be a cross regulation between isoforms (Escherick et al, 1993).…”

“…In skin treated with TPA both expression of TGFb1 and the type II TGF-b receptor is upregulated (Akhurst et al, 1988;Cui et al, 1995;Fowlis et al, 1996). Therefore, it has been suggested that TGF-b plays an important role in skin carcinogenesis (Glick et Glick et al, 1994;Cui et al, 1996).…”

Expression of a dominant-negative type II transforming growth factor β (TGF-β) receptor in the epidermis of transgenic mice blocks TGF-β-mediated growth inhibition

“…Within a given organ, such as the skin, TGF-␤ often has opposite effects on different cell types. For example, TGF-␤ is a potent growth inhibitor of the epidermis, playing an important role in maintenance of tissue homeostasis (3,4), whereas in the dermis, TGF-␤ acts as a positive growth factor, inducing the synthesis of extracellular matrix proteins during wound healing (2,5). TGF-␤ signals through a heteromeric complex of the type I and II TGF-␤ receptors, which have serine͞ threonine kinase activities in their cytoplasmic domains (6,7); however, little is known about how these receptors mediate different biological responses.…”