The research in this proposal continues our studies of the role of glycoproteins in epidermal desquamation, with emphasis on three related serine proteinases that we have isolated from human epidermis (and also find in the more differentiated cells of the oral cavity). Predesquamin (600 kD), immunolocalized to the upper viable layers and the lower stratum corneum, has both thrombin and tryptase activities. It is the precursor of a 400 kD molecule with thrombin activity and of a 40 kD glycoprotein (desquamin) with tryptase activity. Desquamin, immunolocalized to the stratum corneum only, is also a lectin. We showed in cell aggregation experiments that desquamin affects cohesion and desquamation, and we believe that all three molecules are crucial to the degradative events of terminal differentiation. They are not ordinarily expressed in vitro, but we have developed a culture system in which interferon-gamma induces their expression. We will determine to what extent our three enzymes can degrade various structural components of the stratum corneum and whether they act in successive stages. We will elucidate the processing of predesquamin to the other two (and any intermediates) from structural and functional correlations. In particular, we will completely sequence desquamin biochemically, partially sequence the other two, and seek homology with known serine proteinases. Polyclonal antibodies to selected peptides will be used to immunoprecipitate intermediates and for immunolocalization in different cell populations. Given the amino acid sequences of degraded peptides, we will develop oligonucleotide probes to clone for the gene. We will study gene expression, in normal and diseased tissue, and its modulation by agents known to affect proliferation and differentiation, in vitro (with our interferon-gamma system) and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE008477-07
Application #
2130049
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1987-08-01
Project End
1996-02-29
Budget Start
1994-03-01
Budget End
1995-02-28
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Dermatology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Brysk, M M; Lei, G; Adler-Storthz, K et al. (1999) Zinc-alpha2-glycoprotein expression as a marker of differentiation in human oral tumors. Cancer Lett 137:117-20
Arany, I; Tyring, S K; Brysk, H et al. (1998) Induction by interferon-gamma of its receptor varies with epithelial differentiation and cell type. Arch Dermatol Res 290:331-4
Arany, I; Adler-Storthz, K; Chen, Z et al. (1998) Tumor differentiation-dependent local immunity in human head and neck cancers. Cancer Lett 123:173-6
Selvanayagam, P; Lei, G; Bell, T et al. (1998) Desquamin is an epidermal ribonuclease. J Cell Biochem 68:74-82
Yannariello-brown, J; Hallberg, C K; Haberle, H et al. (1998) Cytokine modulation of human corneal epithelial cell ICAM-1 (CD54) expression. Exp Eye Res 67:383-93
Brysk, M M; Lei, G; Adler-Storthz, K et al. (1998) Differentiation and cathepsin D expression in human oral tumors. Laryngoscope 108:1234-7
Brysk, M M; Lei, G; Selvanayagam, P et al. (1997) Modulation by interferon-gamma of zinc-alpha 2-glycoprotein gene expression in human epithelial cell lines. Anticancer Res 17:3387-91
Lei, G; Arany, I; Selvanayagam, P et al. (1997) Detection and cloning of epidermal zinc-alpha 2-glycoprotein cDNA and expression in normal human skin and in tumors. J Cell Biochem 67:216-22
Brysk, M M; Lei, G; Rajaraman, S et al. (1997) Gene expression of zinc-alpha 2-glycoprotein in normal human epidermal and buccal epithelia. In Vivo 11:271-4
Arany, I; Adler-Storthz, K; Chen, Z et al. (1997) Differentiation markers in oral carcinoma cell lines and tumors. Anticancer Res 17:4607-10

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