EPIDERMAL PROLIFERATION OF THE SKIN IN METALLOTHIONEIN-NULL MICE

Metallothionein (MT) is a low-molecular weight metal-binding protein. Although the physiologic function of MT is not fully known, it is pres ent in various species and various organs including the skin. MT is st rongly stained in hyperplastic epidermal tissues in normal skin and in hyperplastic skin lesions, and increased expression of mRNA of the MT gene has been demonstrated in skin stimulated by proliferative agents , suggesting that MT is involved in the proliferation of epidermal ker atinocytes. To improve our understanding of the role of MT in epiderma l hyperplasia, mice with null mutations in their MT-1 and MT-2 genes w ere used in this study. We compared the epidermal hyperplasia in MT-nu ll mice and in normal C57BL/6 J mice after treatments with cholera tox in, 12-0-tetradecanoylphorbol-13-acetate, and ultraviolet B irradiatio n, which stimulate epidermal proliferation. Immunostaining of MT was n ot detected in the skin of MT-null mice, and these mice developed sign ificantly less epidermal hyperplasia than the normal mice after exposu re to each stimulator. We determined the metal contents of skin sample s by the proton-induced x-ray emission method. The zinc content of the skin of the MT-null mice was lower than that of the control mice befo re stimulation. After stimulation of epidermal hyperplasia, MT-null an d normal mice showed significantly reduced levels of zinc. These findi ngs indicate that cellular MT is involved in the proliferative process of the epidermis induced by cholera toxin, 12-0-tetradecanoylphorbol- 13-acetate, and ultraviolet B light through its regulatory action on t he metal metabolism required for cell growth.