The overall emphasis of this research proposal is to learn the growth-associated properties and biochemical structures of the three related human cell surface heterodimers VLA-1, VLA-2 and Alpha3Beta on normal and transformed cells. These heterodimers (210,000/130,000, 165,000/130,000, and 150,000/130,000 Mr respectively) all share a common Beta subunit, but the different Alpha subunits have variable distributions dependent upon cell type and cell growth state. Results from the proposed experiments will 1) lead to insights into novel differences between quiescent, exponential and transformed cells, and 2) provide a novel set of cell surface markers that can be used to evaluate these different stages of cell growth. The detailed specific aims are to: 1) purify the VLA-1, VLA-2 and Alpha3Beta heterodimers for use in monoclonal antibody (MAb) generation and biochemical analyses, 2) generate novel MAb against the different VLA subunits and epitopes, 3) determine the expression of VLA-1, VLA-2 and Alpha3Beta on normal quiscent, normal exponential, and transformed fibroblasts and lymphocytes, with emphasis on studying the radical growth-dependent changes in VLA-1/VLA-2 ratios, 4) test VLA-related MAb for their direct influence on cell growth, function, surface phenotype and morphology, 5) analyze the structure and biosynthesis of the VLA heterodimers, and 6) study the VLA family of proteins on in vivo derived lymphocytes (T cells) from lung and from rheumatoid arthritis patients in order to further understand how these T cells differ from normal peripheral blood T cells. Because the coordinated appearance and disappearance of the different VLA components appears to be closely associated with cell growth and regulation, the health-relatedness and long-term applications are diverse. The fibroblast studies point to applications in the area of transformation and malignancy and the lymphocyte studies point to applications in the area of cellular immunity (eg. autoimmune disease). In regard to applications, MAb to these proteins may be useful for diagnosing and monitoring transformed or activated cells, and eventually may be used to selectively eliminate unwanted or diseased cell populations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA042368-01
Application #
3183579
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1986-05-01
Project End
1989-04-30
Budget Start
1986-05-01
Budget End
1987-04-30
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Sharma, Chandan; Hemler, Martin E (2017) Multiple pro-tumor roles for protein acyltransferase DHHC3. Oncoscience 4:152-153
Ficarro, Scott B; Alexander, William M; Marto, Jarrod A (2017) mzStudio: A Dynamic Digital Canvas for User-Driven Interrogation of Mass Spectrometry Data. Proteomes 5:
Sharma, Chandan; Wang, Hong-Xing; Li, Qinglin et al. (2017) Protein Acyltransferase DHHC3 Regulates Breast Tumor Growth, Oxidative Stress, and Senescence. Cancer Res 77:6880-6890
Wang, Hong-Xing; Sharma, Chandan; Knoblich, Konstantin et al. (2015) EWI-2 negatively regulates TGF-? signaling leading to altered melanoma growth and metastasis. Cell Res 25:370-85
Wang, Hong-Xing; Hemler, Martin E (2015) Novel impact of EWI-2, CD9, and CD81 on TGF-? signaling in melanoma. Mol Cell Oncol 2:
Hemler, Martin E (2014) Tetraspanin proteins promote multiple cancer stages. Nat Rev Cancer 14:49-60
Knoblich, Konstantin; Wang, Hong-Xing; Sharma, Chandan et al. (2014) Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits ?-catenin degradation. Cell Mol Life Sci 71:1305-14
Li, Q; Yang, X H; Xu, F et al. (2013) Tetraspanin CD151 plays a key role in skin squamous cell carcinoma. Oncogene 32:1772-83
Deng, Xinyu; Li, Qinglin; Hoff, John et al. (2012) Integrin-associated CD151 drives ErbB2-evoked mammary tumor onset and metastasis. Neoplasia 14:678-89
Yang, Xiuwei H; Mirchev, Rossen; Deng, Xinyu et al. (2012) CD151 restricts the ?6 integrin diffusion mode. J Cell Sci 125:1478-87

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