Michael T Sturniolo

University of Maryland, Baltimore, Baltimore, Maryland, United States

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Publications (9)38.81 Total impact

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    ABSTRACT: Keratinocytes undergo a process of terminal cell differentiation that results in the construction of a multilayered epithelium designed to produce a structure that functions to protect the body from dehydration, abrasion and infection. These protective properties are due to the production of a crosslinked layer of protein called the cornified envelope. Type I transglutaminase (TG1), an enzyme that catalyzes the formation of epsilon-(gamma-glutamyl)lysine bonds, is the key protein responsible for generation of the crosslinks. The mechanisms that lead to activation of transglutaminase during terminal differentiation are not well understood. We have identified a protein that interacts with TG1 and regulates its activity. This protein, tazarotene-induced gene 3 (TIG3), is expressed in the differentiated layers of the epidermis and its expression is associated with transglutaminase activation and cornified envelope formation. We describe a novel mechanism whereby TIG3 regulates TG1 activity.
    Amino Acids 08/2008; 36(4):739-46. DOI:10.1007/s00726-008-0123-9 · 3.65 Impact Factor
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    Ralph Jans, Michael T Sturniolo, Richard L Eckert
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    ABSTRACT: Tazarotene-induced gene 3 (TIG3) regulates keratinocyte terminal differentiation by activating type I transglutaminase (TG1). TIG3 consists of an amino-terminal (N-terminal) segment, that encodes several conserved motifs, and a carboxy-terminal (C-terminal) membrane-anchoring domain. By producing a series of truncation mutants that remove segments of the N-terminal region, and monitoring the ability of each mutant to co-precipitate TG1, function as a TG1 substrate, or functionally localize with TG1 in cells, we show that the TIG3 domain that interacts with TG1 is located within a TIG3 segment spanning amino acids 112-164. Although they bind TG1, TIG3 mutants lacking the conserved N-terminal region drive apoptosis-like cell death characterized by cell rounding, membrane blebbing, cytochrome c release, procaspase-3 and poly(ADP-ribose)polymerase (PARP) cleavage, and reduced p53 and p21 levels. Compared with TIG3, these truncated mutants have an increased tendency to associate with membranes. A mutant lacking the C-terminal membrane-anchoring domain is inactive. These findings suggest that TIG3 interaction with TG1 does not require the N-terminal conserved domains, that the TIG3 N-terminal region is required for TIG3-dependent keratinocyte differentiation, that its removal converts TIG3 into a proapoptotic protein, and that this change in action of TIG3 is associated with an intracellular redistribution.
    Journal of Investigative Dermatology 04/2008; 128(3):517-29. DOI:10.1038/sj.jid.5701035 · 6.37 Impact Factor
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    ABSTRACT: Epigallocatechin-3-gallate (EGCG) is an important chemopreventive agent derived from green tea. We recently reported that EGCG treatment enhances keratinocyte differentiation as evidenced by increased human involucrin promoter activity [Balasubramanian,S., Efimova,T. and Eckert,R.L. (2002) J. Biol. Chem., 277, 1828-1836]. In the present paper, we extend these findings and show that EGCG also increases the expression of other differentiation markers-procaspase 14 and type I transglutaminase (TG1). Both TG1 mRNA and protein level, and activity are increased by treatment with EGCG. Increased TG1 activity is evidenced by a direct transglutaminase assay, and by the ability of EGCG to stimulate the covalent incorporation of fluorescein cadaverine substrate into crosslinked intracellular structures. In contrast, type II transglutaminase levels are not altered by EGCG treatment. We also assessed whether EGCG promotes keratinocyte apoptosis. We show that EGCG treatment does not promote the cleavage of procaspase-3, -8, -9 or poly(ADP-ribose) polymerase. Moreover, treatment with the pan-caspase inhibitor, Z-VAD-FMK, does not reverse the EGCG-associated reduction in cell viability. In addition, there is no increase in cells having sub-G(1)/S DNA content, and no evidence for the release of cytochrome c from the mitochondria. These findings confirm, using several endpoints, that EGCG treatment enhances normal keratinocyte differentiation but does not promote apoptosis.
    Carcinogenesis 07/2005; 26(6):1100-8. DOI:10.1093/carcin/bgi048 · 5.27 Impact Factor
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    ABSTRACT: Type I transglutaminase is a plasma membrane-anchored intracellular protein-protein crosslinking enzyme that is responsible for assembly of the keratinocyte cornified envelope during terminal keratinocyte differentiation. We recently described a novel protein, TIG3, that when expressed in keratinocytes causes increased transglutaminase activity and keratinocyte cell death. However, the mechanism of activation of transglutaminase by TIG3 is not known. We now extend our previous study and show that full-length TIG3 forms a complex with type I transglutaminase that is demonstrated by TIG3-transglutaminase co-precipitation. We also demonstrate that treating TIG3-expressing cells with monodansyl cadaverine, a competitive transglutaminase substrate, attenuates the TIG3-dependent response, suggesting that transglutaminase is an important mediator of TIG3 action. These findings suggest that TIG3 forms a complex with transglutaminase resulting in transglutaminase activation and that transglutaminase activity is required for the TIG3-dependent biological response.
    Oncogene 05/2005; 24(18):2963-72. DOI:10.1038/sj.onc.1208392 · 8.56 Impact Factor
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    ABSTRACT: Surface epithelial cells, such as the epidermal keratinocyte, undergo a process of terminal cell differentiation that results in the construction of a multilayered epithelium. This epithelium functions to protect the organism from the environment. Transglutaminases, enzymes that catalyze the formation of isopeptide protein-protein cross-links, are key enzymes involved in the construction of this structure. This brief review will focus on the role of these enzymes in constructing the epidermal surface.
    Journal of Investigative Dermatology 04/2005; 124(3):481-92. DOI:10.1111/j.0022-202X.2005.23627.x · 6.37 Impact Factor
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    Progress in experimental tumor research. Fortschritte der experimentellen Tumorforschung. Progrès de la recherche expérimentale des tumeurs 02/2005; 38:115-24. DOI:10.1159/000084236 · 0.25 Impact Factor
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    ABSTRACT: Tazarotene-induced protein 3 (TIG3) is a recently discovered regulatory protein that is expressed in the suprabasal epidermis. In the present study, we show that TIG3 regulates keratinocyte viability and proliferation. TIG3-dependent reduction in keratinocyte viability is accompanied by a substantial increase in the number of sub-G1 cells, nuclear shrinkage, and increased formation of cornified envelope-like structures. TIG3 localizes to the membrane fraction, and TIG3-dependent differentiation is associated with increased type I transglutaminase activity. Microscopic localization and isopeptide cross-linking studies suggest that TIG3 and type I transglutaminase co-localize in membranes. Markers of apoptosis, including caspases and poly(ADP-ribose) polymerase, are not activated by TIG3, and caspase inhibitors do not stop the TIG3-dependent reduction in cell viability. Truncation of the carboxyl-terminal membrane-anchoring domain results in a complete loss of TIG3 activity. The morphology of the TIG3-positive cells and the effects on cornified envelope formation suggest that TIG3 is an activator of terminal keratinocyte differentiation. Our studies suggest that TIG3 facilitates the terminal stages in keratinocyte differentiation via activation of type I transglutaminase.
    Journal of Biological Chemistry 12/2003; 278(48):48066-73. DOI:10.1074/jbc.M307215200 · 4.60 Impact Factor
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    ABSTRACT: The epidermis is a dynamic and continually renewing surface that provides and maintains a life-sustaining interface with the environment. The epidermal keratinocyte, the major cell type of the epidermis, undergoes a complex and carefully choreographed program of differentiation. This process requires a balance between keratinocyte proliferation, differentiation, and apoptosis. This overview will concentrate on cascades that regulate the balance between keratinocyte cell proliferation and survival, and apoptosis and cell differentiation, with a particular emphasis on the role of the mitogen-activated protein kinase cascades. A summary of the literature suggests that extracellular regulated kinases function to promote keratinocyte proliferation and survival, whereas p38 mitogen-activated protein kinase functions to promote differentiation and apoptosis.
    Journal of Investigative Dermatology Symposium Proceedings 01/2003; 7(1):36-40. DOI:10.1046/j.1523-1747.2002.19634.x · 3.73 Impact Factor
  • Michael Thomas Sturniolo