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The calcium sensing receptor and its alternatively spliced form in murine epidermal differentiation

JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第2期275卷 1183-1190页

作者： Oda, Y Tu, CL Chang, WH Crumrine, D Kömüves, L Mauro, T Elias, PM Bikle, DD Univ Calif San Francisco Vet Affairs Med Ctr Dept Med & Dermatol San Francisco CA 94121 USA Univ Calif San Francisco Vet Affairs Med Ctr Dept Endocrinol San Francisco CA 94121 USA

We have recently reported that human keratinocytes express both the full-length calcium sensing receptor (CaR) and an alternatively spliced form lacking exon 5, which were suggested to be involved in calcium induced keratinocyte differentiation. To understand further the role of these CaRs, we analyzed the structure of mouse CaRs, and investigated their role using a mouse model in which only the full-length CaR was disrupted. Our results show that both the full-length and the alternatively spliced variant lacking exon 5 encoding 77 amino acids of the extracellular domain were expressed in mouse epidermis. The deletion of the full-length CaR increased the production of the alternatively spliced form of CaR in mutant mice. The keratinocytes derived from these mutant mice did not respond to extracellular calcium, suggesting that the full-length CaR is required to mediate calcium signaling in the keratinocytes. The loss of the full-length CaR altered the morphologic appearance of the epidermis and resulted in a reduction of the mRNA and protein levels of the keratinocyte differentiation marker, loricrin. These results indicate that CaR is important in epidermal differentiation, and that the alternatively spliced form does not fully compensate for loss of the full-length CaR.

关键词：选择性剪接氨基酸序列动物新生碱基序列钙/代谢细胞分化细胞系细胞培养的克隆分子表皮/生理学角蛋白细胞/细胞学角蛋白细胞/生理学小鼠基因敲除分子序列数据受体钙敏感受体细胞表面/化学受体细胞表面/遗传学受体细胞表面/生理学重组蛋白质类/化学重组蛋白质类/代谢逆转录聚合酶链反应序列比对序列同源性氨基酸皮肤/细胞学皮肤/代谢转染动物牛人类小鼠

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Transgenic expression of cyclin-dependent kinase 4 results in epidermal hyperplasia, hypertrophy, and severe dermal fibrosis

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AMERICAN JOURNAL OF PATHOLOGY 2001年第1期159卷 369-379页

作者： de Marval, PLM Gimenez-Conti, IB LaCava, M Martinez, LA Conti, CJ Rodriguez-Puebla, ML Univ Texas MD Anderson Hosp & Tumor Inst Sci Pk Res Div Smithville TX 78957 USA Univ Texas MD Anderson Hosp & Tumor Inst Dept Carcinogenesis Smithville TX 78957 USA

In a previous report we have described the effects of expression of D-type cyclins in epithelial tissues of transgenic mice. To study the involvement of the D-type cyclin partner cyclin-dependent kinase 4 (CDK4) In epithelial growth and differentiation, transgenic mice were generated carrying the CDK4 gene under the control of a keratin 5 promoter. As expected, transgenic mice showed expression of CDK4 in the epidermal basal-cell layer. Epidermal proliferation increased dramatically and basal cell hyperplasia and hypertrophy were observed. The hyperproliferative phenotype of these transgenic mice was independent of D-type cyclin expression because no overexpression of these proteins was detected. CDK4 and CDK2 kinase activities increased in transgenic animals and were associated with elevated binding of p27(Kip1) to CDK4. Expression of CDK4 in the epidermis results in an increased spinous layer compared with normal epidermis, and a mild hyperkeratosis in the cornified layer. In addition to epidermal changes, severe dermal fibrosis was observed and part of the subcutaneous adipose tissue was replaced by connective tissue. Also, abnormal expression of keratin 6 associated with the hyperproliferative phenotype was observed in transgenic epidermis. This model provides in vivo evidence for the rot of CDK4 as a mediator of proliferation in epithelial cells independent of D-type cyclin expression.

关键词：细胞周期蛋白依赖激酶4 细胞周期蛋白质依赖激酶类/遗传学细胞周期蛋白质依赖激酶类/代谢细胞周期蛋白质依赖激酶类/生理学细胞周期蛋白类/代谢表皮/代谢表皮/病理学表皮/生理学纤维化增生肥大角蛋白质类/代谢小鼠转基因/遗传学原癌基因蛋白质类视网膜母细胞瘤蛋白质/代谢皮肤/代谢皮肤/病理学动物人类小鼠

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Caveolin-1 and-2 expression is differentially regulated in cultured keratinocytes and within the regenerating epidermis of cutaneous wounds

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EXPERIMENTAL CELL RESEARCH 2000年第1期258卷 23-32页

作者： Gassmann, MG Werner, S Max Planck Inst Biochem D-82152 Martinsried Germany ETH Honggerberg Inst Cell Biol CH-8093 Zurich Switzerland

Keratinocyte growth factor (KGF) and its receptor are involved in various types of epithelial repair processes. To gain insight into the molecular mechanisms of KGF action in the healing skin mound, we searched for genes which are regulated by this factor in cultured keratinocytes. Using the PCR-select technology we constructed a subtractive cDNA library. One of the KGF-regulated genes that we identified was shown to encode caveolin-1, a major component of caveolar membranes. Caveolin-1 is involved in a nide variety of cellular processes, particularly in the regulation of various signal transduction pathways. Caveolin-1 mRNA levels increased in cultured keratinocytes after KGF treatment. By in situ hybridization and immunohistochemistry we found a strong expression of caveolin-1 in the KGF-responsive basal keratinocytes of the epidermis and the hyperproliferative epithelium of the mound as well as in endothelial cells and in other cells of the granulation tissue. In 13-day wounds expression of caveolin-1 mRNA was restricted to the regenerated dermis, In addition to caveolin-1, the mRNA expression of caveolin-2, a second member of the caveolin family, was also induced in keratinocytes after stimulation with KGF but also with other growth factors and cytokines. In contrast to caveolin-1, caveolin-2 protein was expressed in all layers of the normal epidermis and in the suprabasal layers of the hyperproliferative wound epithelium. These results demonstrate a differential expression of caveolin-1 and -2 in proliferating versus differentiating keratinocytes. (C) 2000 Academic Press.

关键词：窖蛋白1 窖蛋白2 细胞质膜微囊蛋白细胞系表皮生长因子/药理学表皮/生理学表皮/病理生理学成纤维细胞生长因子10 成纤维细胞生长因子7 成纤维细胞生长因子荧光抗体技术间接基因表达调控/药物作用基因表达调控/生理学基因文库生长物质/药理学生长物质/生理学角蛋白细胞/生理学膜蛋白质类/分析膜蛋白质类/遗传学小鼠近交BALBC RNA 信使/遗传学皮肤/损伤转录遗传转化生长因子β/药理学肿瘤坏死因子α/药理学伤口愈合/药物作用伤口愈合/遗传学动物人类小鼠

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Modeling of diffusion and concurrent metabolism in cutaneous tissue

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JOURNAL OF THEORETICAL BIOLOGY 2000年第3期204卷 393-407页

作者： Boderke, P Schittkowski, K Wolf, M Merkle, HP ETH Zurich Galen Pharm Dept Appl Biosci Drug Formulat & Delivery CH-8057 Zurich Switzerland Univ Bayreuth Dept Math D-95440 Bayreuth Germany Univ Bonn Dept Pharm D-53121 Bonn Germany

Clearance by cutaneous metabolism can shield the body from penetration of environmental and therapeutic xenobiotics. Here we report on a physical model to relate Fickian diffusion and concurrent Michaelis-Menten metabolism of drugs in the viable epidermis of human skin. For this purpose, we numerically generated substrate concentration profiles within the metabolizing tissue and the resulting donor-to-receiver substrate fluxes through the tissue for various mass transport and metabolism parameters. To validate the model, permeation and concurrent metabolism of a peptidomimetic compound, L-Ala-4-methoxy-2-naphthylamide (Ala-MNA), across both stripped human skin and HaCaT cell culture sheets were compared to numerical simulations. Parameter estimates for those calculations were extracted from independent experiments. Experimental data and numerical predictions were in excellent agreement. Also, numerical fits and independently validated parameters correlated closely, indicating the principal validity of the physical model. Numerical simulations and theoretical derivations illustrate the kinetic impact of the factors involved, i.e. the diffusion coefficient D, substrate donor concentration C-S,C-D, substrate partition coefficient P, tissue thickness L and maximum metabolic rate V-max, on drug permeation, with L having the strongest effect. In the steady state, the coefficient 2 alpha, i.e. the dimensionless ratio of the residence time term (L-2/D) of a substrate in the tissue to the metabolic half-life term (C-S,C-D P/2V(max)), allows to estimate concentration gradients within the tissue and the extent of metabolism. High 2a values represent practically complete metabolic cleavage upon penetration. Epidermis (similar to 40 mu m thick) of stripped human skin and HaCaT sheets (similar to 10 mu m) had 2 alpha values of 43 and 2.7, respectively, indicating that intact Ala-MNA could only permeate HaCaT sheets, but not skin. Independent permeation experiments confirmed this

关键词：细胞培养的扩散表皮/代谢表皮/生理学模型生物学异生物质/代谢人类

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Mesenchyme with fgf-10 expression is responsible for regenerative capacity in Xenopus limb buds

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DEVELOPMENTAL BIOLOGY 2000年第1期219卷 18-29页

作者： Yokoyama, H Yonei-Tamura, S Endo, T Belmonte, JCI Tamura, K Ide, H Tohoku Univ Grad Sch Sci Inst Biol Sendai Miyagi 9808578 Japan Salk Inst Biol Studies Gene Express Lab La Jolla CA 92037 USA

A young tadpole of an anuran amphibian can completely regenerate an amputated limb, and it exhibits an ontogenetic decline in the ability to regenerate its limbs. However, whether mesenchymal or epidermal tissue is responsible for this decrease of the capacity remains unclear. Moreover, little is known about the molecular interactions between these two tissues during regeneration. The results of this study showed that fgf-10 expression in the limb mesenchymal cells clearly corresponds to the regenerative capacity and that fgf-10 and fgf-8 are synergistically reexpressed in regenerating blastemas. However, neither fgf-10 nor fgf-8 is reexpressed after amputation of a nonregenerative limb. Nevertheless, nonregenerative epidermal tissue can reexpress fgf-8 under the influence of regenerative mesenchyme, as was demonstrated by experiments using a recombinant limb composed of regenerative limb mesenchyme and nonregenerative limb epidermis. Taken together, our data demonstrate that the regenerative capacity depends on mesenchymal tissue and suggest that fgf-10 is likely to be involved in this capacity. (C) 2000 Academic Press.

关键词：氨基酸序列嵌合体/遗传学嵌合体/生理学表皮/生理学四肢/生理学成纤维细胞生长因子10 成纤维细胞生长因子8 成纤维细胞生长因子/遗传学基因表达调控发育期原位杂交幼虫/遗传学幼虫/生长和发育幼虫/生理学中胚层/生理学分子序列数据再生/遗传学序列同源性氨基酸爪蟾属/遗传学爪蟾属/生长和发育爪蟾属/生理学爪蟾蛋白质类动物人类

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The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第8期96卷 4680-4685页

作者： Schwartz, DR Homanics, GE Hoyt, DG Klein, E Abernethy, J Lazo, JS Univ Pittsburgh Dept Pharmacol Pittsburgh PA 15261 USA Univ Pittsburgh Dept Anesthesiol Crit Care Med Pittsburgh PA 15261 USA Univ Pittsburgh Dept Pathol Pittsburgh PA 15261 USA Univ Pittsburgh Div Lab Anim Resources Pittsburgh PA 15261 USA

The papain superfamily member bleomycin hydrolase (Blmh) is a neutral cysteine protease with structural similarity to a 20S proteasome. Bleomycin (BLM), a clinically used glycopeptide anticancer agent, is deaminated in vitro by Blmh. We used gene targeting to generate mice that lack Blmh and demonstrated that Blmh is the sole enzyme required for BLM deamination. Although some Blmh null mice were viable and reproduced, only about 65% of the expected number survived the neonatal period, revealing an important role for Blmh in neonatal survival. Mice lacking Blmh exhibited variably penetrant tail dermatitis that resembled rodent ringtail. The histopathology of the tail dermatitis was similar to skin lesions in humans with pellagra, necrolytic migratory erythema, and acrodermatitis enteropathica, Compared with controls, Blmh null mice were more sensitive to acute ELM lethality and developed pulmonary fibrosis more readily following BLM treatment. Thus, we have established that Blmh is an essential protectant against BLM-induced death and has an important role in neonatal survival and in maintaining epidermal integrity.

关键词：衰老动物新生博来霉素/药代动力学博来霉素/毒性半胱氨酸内肽酶类/缺乏半胱氨酸内肽酶类/遗传学半胱氨酸内肽酶类/代谢皮炎/遗传学皮炎/病理学抗药性/遗传学表皮/病理学表皮/生理学小鼠基因敲除限制性内切酶图谱法皮肤/药物作用皮肤/病理学动物人类小鼠

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Pore charge distribution considerations in human epidermal membrane electroosmosis

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JOURNAL OF PHARMACEUTICAL SCIENCES 1999年第10期88卷 1044-1049页

作者： Li, SK Ghanem, AH Higuchi, WI Univ Utah Dept Pharmaceut & Pharmaceut Chem Salt Lake City UT 84112 USA

The aim of this study was to assess the extent to which a model with pores having only net negative charges would adequately describe transdermal electroosmosis in human epidermal membrane (HEM) at neutral pH. Such information would enhance the predictive value of the modified Nernst-Planck model for transdermal iontophoresis, in addition to providing insights regarding the likelihood of significant pore charge distribution in HEM. Baseline results (the control) obtained from 0.1 to 0.4 V anodal and cathodal electroosmosis experiments with synthetic polycarbonate membranes (Nuclepore membranes), using radiolabeled urea and mannitol as the model permeants, demonstrated that such a membrane system can be modeled by the electrokinetic (electroosmosis) theory with the assumption of the pores possessing only negative charges. The studies with HEM were carried out at low voltage (less than or similar to 0.5 V) where alterations in the barrier properties of HEM were minimal and at higher voltages (greater than or similar to 1.0 V) where significant field-induced pore formation in HEM occurred. In both the low and high voltage studies, radiolabeled urea, mannitoll and water were employed as permeants in cathodal and anodal iontophoresis experiments. The results of the low voltage iontophoresis experiments suggest significant pore charge distribution in HEM (a significant deviation between the predictions from the single pore charge type assumption and the experimental data). Under the higher applied voltage conditions (greater than or similar to 1.0 V), results from anodal and cathodal electroosmosis studies were consistent with the model in which the HEM has only pores that are net negatively charged.

关键词：算法缓冲剂细胞膜通透性表皮/生理学氢离子浓度离子透入法甘露醇/代谢渗透磷酸盐类/化学溶剂尿素/化学水/代谢人类

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Klf4 is a transcription factor required for establishing the barrier function of the skin

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NATURE GENETICS 1999年第4期22卷 356-360页

作者： Segre, JA Bauer, C Fuchs, E Univ Chicago Howard Hughes Med Inst Dept Mol Genet & Cell Biol Chicago IL 60637 USA

Located at the interface between body and environment, the epidermis must protect the body against toxic agents and dehydration, and protect itself against physical and mechanical stresses(1-4). Acquired just before birth and at the last stage of epidermal differentiation, the skin's proteinaceous/lipid barrier creates a surface seal essential for protecting animals against microbial infections and dehydration. We show here that Kruppel-like factor 4 (Klf4, encoded by the gene Klf4), highly expressed in the differentiating layers of epidermis, is both vital to and selective for barrier acquisition. Klf4(-/-) mice die shortly after birth due to loss of skin barrier function, as measured by penetration of external dyes and rapid loss of body fluids. The defect was not corrected by grafting of Klf4(-/-) skin onto nude mice. Loss of the barrier occurs without morphological and biochemical alterations to the well-known structural features of epidermis that are essential for mechanical integrity. Instead, late-stage differentiation structures are selectively perturbed, including the cornified envelope, a likely scaffold for lipid organization. Using suppressive subtractive hybridization, we identified three transcripts encoding cornified envelope proteins with altered expression in the absence of Klf4. Sprr2a is one, and is the only epidermal gene whose promoter is known to possess a functional Klf4 binding site. Our studies provide new insights into transcriptional governance of barrier function, and pave the way for unravelling the molecular events that orchestrate this essential process.

关键词：体重 DNA结合蛋白质类表皮/解剖学和组织学表皮/胚胎学表皮/生理学表皮/超微结构 Kruppel样转录因子类小鼠裸显微镜检查免疫电子模型遗传学诱变皮肤移植时间因素舌/解剖学和组织学舌/胚胎学转录因子/分析转录因子/代谢转录因子/生理学动物小鼠

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Development of keratoacanthomas and squamous cell carcinomas in transgenic rabbits with targeted expression of EJras oncogene in epidermis

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AMERICAN JOURNAL OF PATHOLOGY 1999年第1期155卷 315-324页

作者： Peng, XW Griffith, JW Han, RC Lang, CM Kreider, JW Penn State Univ Milton S Hershey Med Ctr Dept Comparat Med Hershey PA 17033 USA Penn State Univ Milton S Hershey Med Ctr Jake Gittlen Canc Res Inst Hershey PA 17033 USA Penn State Univ Milton S Hershey Med Ctr Dept Microbiol & Immunol Hershey PA 17033 USA

Activated ras genes have been frequently identified in both benign and malignant human tumors, including keratoacanthoma and squamous cell carcinoma. In this study, we developed two lines of transgenic rabbits in which the expression of EJras has been specifically targeted to the rabbit epidermal keratinocytes, using the upstream regulatory region of cottontail rabbit papillomavirus. All of the F1 transgenic progenies developed multiple keratoacanthomas at about 3 days after birth. The rabbits developed an average of 20 tumors, which usually reached the size of approximately 1 cm in diameter and then spontaneously regressed in about 2 months, similar to keratoacanthoma regression in humans. In addition, up to 18% of the rabbits then developed squamous cell carcinoma at about 5 months of age. The expression of EJras was detectable in all of the keratoacanthomas and squamous cell carcinomas. These results strongly support the involvement of the ras oncogene in both the initiation and regression of keratoacanthoma, and in the development of squamous cell carcinomas. These novel transgenic rabbits, with their consistent tumorigenic phenotype at an early age, high similarity to the human lesions, and easy accessibility for examination, manipulation, biopsy, and treatment, should provide a unique model system for studying ras activation-related tumor initiation, regression, and progression, and for evaluating antitumor therapies.

关键词：动物基因修饰/遗传学癌鳞状细胞/遗传学癌鳞状细胞/病理学表皮/生理学基因表达/生理学角化棘皮瘤/遗传学角化棘皮瘤/病理学癌基因蛋白质类/遗传学皮肤肿瘤/遗传学皮肤肿瘤/病理学转基因/遗传学动物男(雄)性兔

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The importance of L-phenylalanine transport and its autocrine turnover to L-tyrosine for melanogenesis in human epidermal melanocytes

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第2期262卷 423-428页

作者： Schallreuter, KU Wood, JM Univ Bradford Dept Biomed Sci Bradford BD7 1DP W Yorkshire England Univ Greifswald Biotechnikum Pigmentary Disorders eV D-17489 Greifswald Germany

A comparative study of C-14-labeled L-phenylalanine and H-3-labeled L-tyrosine uptake in cultures of human melanocytes (n = 8) and keratinocytes (n = 2) identified a significantly more rapid active transport for L-phenylalanine in melanocytes, whereas the slower uptake of L-tyrosine followed a concentration-dependent gradient, confirming facilitated diffusion rather than active transport. In addition, a significantly more efficient autocrine turnover of L-phenylalanine to L-tyrosine via intracellular phenylalanine hydroxylase was demonstrated in melanocytes. The incorporation of the newly synthesized radiolabeled L-tyrosine was directly followed into the end product melanin. The presence of L-phenylalanine in the culture medium produced 40% more melanin compared to an equivalent concentration of L-tyrosine alone. The transport of extracellular L-phenylalanine and its intracellular metabolism to L-tyrosine via intracellular phenylalanine hydroxylase are coupled to calcium uptake/efflux, whereas L-tyrosine uptake is calcium independent. Taken together, our results identified for the first time the importance of autocrine calcium-dependent active L-phenylalanine uptake/turnover in melanocytes as a major pathway for melanogenesis. (C) 1999 Academic Press.

关键词：自身分泌性细胞间通讯生物转运/药物作用钙/药理学细胞培养的表皮/细胞学表皮/生理学内环境稳定黑素类/生物合成黑素细胞/生理学苯丙氨酸/代谢苯丙氨酸羟化酶/代谢酪氨酸/代谢女(雌)性人类男(雄)性

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