Jon Richard Wiener, Ph.D.
My laboratory is interested in the roles that protein tyrosine kinases (PTK) and phosphatases (PTP) play in regulating the growth, oncogenic potential, and metastatic capability of human ovarian and breast cancer cells. The aberrant expression of receptor (e.g., HER-2/neu) and nonreceptor (e.g., c-src) PTK is one of numerous well-documented genetic alterations that influence the development of cancers from normal epithelium. In contrast, PTP, which act as biochemical antagonists of tyrosine phosphorylation, may have great influence on PTK-mediated signaling but are as yet a greatly understudied family of molecules. Since the extent of tyrosine phosphorylation observed in any cell is the net result of the activities of both PTK and PTP working in concert, we have been interested in expanding our understanding of PTK signaling pathways in the context of the PTP that interface with relevant PTK or their substrates.

Studies are currently under way to investigate the role that overexpression of the human proto-oncogene c-src plays in the regulation of human ovarian cancer cell growth. This project, done in collaboration with Dr. Gary Gallick (Department of Cancer Biology), illustrated that alteration of c-src activity greatly influences the tumorigenic potential of metastatic ovarian cancer cells. This is a suitable experimental model system to investigate not only altered signaling via c-src but also the effect of this alteration on the PTPs that putatively interface with c-src, e.g., PTP1B, SHP-1, SHP-2, and rPTPalpha. Since c-src tightly associates with the HER-2/neu receptor PTK in vivo, this system also provides potential inroads to understanding how HER-2/neu influences cell growth and tumorigenesis. Finally, we are utilizing this system to investigate the role that c-src plays in modulating the expression and secretion of invasive or angiogenic factors from metastatic ovarian cancer cells.

Other current investigations include (a) growth regulation of human breast cancer cells by the SH2-containing PTP SHP-1, in collaboration with Dr. Gordon Mills (this department); (b) modulation of secretion of invasive factors from ovarian cancer cells by lysophosphatidic acid, in collaboration with Dr. Mills; and (c) the role of HER-2/neu tyrosine phosphorylation in modulating HER-2/neu-specific, T-cell-mediated cytotoxicity, in collaboration with Dr. Constantin Ioannides (Department of Gynecologic Oncology).

Assistant Professor of Experimental Surgery (NT)      Department of Surgery
     Duke University Medical Center
     Durham, NC

1. J. R. Wiener, R. Pal, Y. Barenholz, and R. R. Wagner. Influence of the Peripheral Matrix Protein of Vesicular Stomatitis Virus on the Membrane Dynamics of Mixed Phospholipid Vesicles: Fluorescence Studies. Biochemistry 22:2162-2170, 1983.

2. R. Pal, J. R. Wiener, Y. Barenholz, and R. R. Wagner. Influence of the Membrane Glycoprotein and Cholesterol of Vesicular Stomatitis Virus on the Dynamics of Viral and Model Membranes: Fluorescence Studies. Biochemistry 22:3624-3630, 1983.

3. J. R. Wiener, R. R. Wagner, and E. Freire. Thermotropic Behavior of Mixed Phospha- tidylcholine-Phosphatidylglycerol Vesicles Reconstituted with the Matrix Protein of Vesicular Stomatitis Virus. Biochemistry 22:6117-6123, 1983.

4. R. Pal, B. W. Grinnell, R. M. Snyder, J. R. Wiener, W. A. Volk, and R. R. Wagner. Monoclonal Antibodies to the M Protein of Vesicular Stomatitis Virus (Indiana Serotype) and to a cDNA M Gene Expression Product. J. Virol 55:298-306, 1985.

5. J. R. Wiener, R. Pal, Y. Barenholz, and R. R. Wagner. Effect of the Vesicular Stomatitis Virus Matrix Protein on the Lateral Organization of Lipid Bilayers Containing Phosphatidyl-glycerol: Use of Fluorescent Phospholipid Analogues. Biochemistry 24:7651-7658, 1985.

6. W. Cashdollar, R. A. Chmelo, J. R. Wiener, and W. K. Joklik. Sequences of the S1 Genes of the Three Serotypes of Reovirus. Proc. Natl. Acad. Sci. USA 82:24-28, 1985.

7. J. R. Wiener and W. K. Joklik. Comparison of the Reovirus Serotype 1,2, and 3 S3 Genome Segments Encoding the Nonstructural Protein Sigma NS. Virology 161:332- 339, 1987.

8. J. R. Wiener and W. K. Joklik. Evolution of Reovirus Genes: A Comparison of Serotype 1,2, and 3 M2 Genome Segments, Which Encode the Major Structural Capsid Protein Mu1C. Virology 163:603-613, 1988.

9. J. R. Wiener and W. K. Joklik. The Sequences of the Reovirus Serotype 1, 2, and 3 L1 Genome Segments and Analysis of the Mode of Divergence of the Reovirus Serotypes. Virology 169:194-203, 1989.

10. J. R. Wiener, J. A. Bartlett, and W. K. Joklik. The Sequences of Reovirus Serotype 3 Genome Segments M1 and M3 Encoding the Minor Protein Mu2 and the Major Nonstructural Protein MuNS, Respectively. Virology 169:293-304, 1989.

11. J. R. Wiener, T. McLaughlin, and W. K. Joklik. The Sequences of the S2 Genome Segments of Reovirus Serotype 3 and of the dsRNA-Negative Mutant ts447. Virology 170:340-341, 1989.

12. K. R. Kidd, B.J. Kerns, R. K. Dodge, and J. R. Wiener. Histochemical Staining of Protein-Tyrosine Phosphatase Activity in Primary Human Mammary Carcinoma: Relationship with Known Prognostic Indicators. J. Histochem. Cytochem. 40:729-735, 1992.

13. G. Huper, J. R. Marks, J. R. Wiener, and J. D. Iglehart. Relative Promoter Activity in Human Mammary Epithelial Cells Assayed by Transient Expression. In Vitro Cell. Dev. Biol. 28A:730-734, 1992.

14. R. C. Bast, Jr., C. M. Boyer, I. Jacobs, F. Xu, S. Wu, J. Wiener, M. Kohler, and A. Berchuck. Cell Growth Regulation in Epithelial Ovarian Cancer. Cancer 71:1597-1601, 1993.

15. S. Wu, C. M. Boyer, R. Whitaker, A. Berchuck, J. R. Wiener, J. B. Weinberg, and R. C. Bast Jr. Tumor Necrosis Factor-alpha (TNF-alpha) as an Autocrine and Paracrine Growth Factor for Ovarian Cancer: Monokine Induction of Tumor Cell Proliferation and TNF-alpha Expression. Cancer Res 53:1939-1944, 1993.

16. J. R. Wiener, B-J M. Kerns, E.L. Harvey, M. R. Conaway, J. D. Iglehart, A. Berchuck, and R. C. Bast, Jr. Overexpression of the Protein Tyrosine Phosphatase PTP1B in Human Breast Cancer: Association with p185c-erbB-2 Protein Expression. J. Natl. Canc. Inst. 86: 372-378, 1994.

17. R. C. Bast Jr, C. M. Boyer, F. Xu, S. Wu, J. R. Wiener, S. K. Kassim, M. F. Kohler, K. O'Briant, K. DeSombre, B. S. Bast, G. S. Dean, L. Daly, and A. Berchuck. Selected Molecular Targets for Diagnosis and Therapy of Epithelial Ovarian Cancer (Review). Canc. Mol. Biol. 1:87-93, 1994.

18. S. Kassim, J. R. Wiener, A. Berchuck, and R. C. Bast, Jr. Protein Tyrosine Phosphatases: Biology and Role in Human Cancers (Review). Canc. Mol. Biol. 1:133- 144, 1994.

19. J. R. Wiener, J. A. Hurteau, B-J. M. Kerns, R. Whitaker, M. R. Conaway, S. Wu, A. Berchuck, and R. C. Bast, Jr. Overexpression of the Tyrosine Phosphatase PTP1B is Associated with Human Ovarian Carcinomas. Am. J. Obstet. Gynecol. 170:1177-1183, 1994.

20. S. Wu, W. A. Meeker, J. R. Wiener, A. Berchuck, R. C. Bast, Jr., and C. M. Boyer. Transfection of Ovarian Cancer Cells with Tumor Necrosis Factor-alpha (TNF-alpha) Antisense mRNA Abolishes the Proliferative Response to Interleukin-1 (IL-1) but not TNF-alpha. Gynecol. Oncol. 53:59-63, 1994.

21. R. C. Bast, Jr., C.M. Boyer, F.J. Xu, J. Wiener, R. Dabel, R. Woolas, I. Jacobs, and A. Berchuck. Molecular Approaches to Prevention and Detection of Epithelial Ovarian Cancer. J. Cell. Biochem. (Suppl 23):219-222, 1995.

22. J. R. Wiener, S. K. Kassim, Y. Yu, G. B. Mills, and R. C. Bast, Jr. Transfection of Human Ovarian Cancer Cells with the HER-2/neu Receptor Tyrosine Kinase Induces a Selective Increase in PTPH1, PTP1B, and PTP Expression. Gynecol. Oncol. 61:233- 240, 1996.

23. C. van Haaften Day, P. Russell, C. M. Boyer, B-J. M. Kerns, J. Wiener, D. N. Jensen, R. C. Bast, Jr., and N. F. Hacker. Expression of Cell Regulatory Proteins in Ovarian Epithelial-Stromal Tumors. Cancer 77:2092-2098, 1996.

24. S. Fayed, S. Wu, Y. Lidor, M. Super, A. Berchuck, R.C. Bast, Jr. and J. R. Wiener. Detection and Partial Purification of a 30 kDa Ovarian Carcinoma-Associated Protein. Canc. Mol. Biol. 3:915-926, 1996.

25. R. Orlandi, C. Formantici, S. Menard, C. M. Boyer, J. R. Wiener, M. I. Colnaghi. A Linear Region of a Monoclonal Antibody Conformational Epitope Mapped on p185HER2 Oncoprotein. Biol. Chem. 378:1387-1392, 1997.

26. C. M. Boyer, L. Pusztai, J. R. Wiener, F. Xu, G. S. Dean, B. S. Bast, K. C. O'Briant, M. Greenwald, K. A. DeSombre, and R. C. Bast, Jr. Relative Cytotoxic Activity of Immunotoxins Reactive with Different Epitopes on the Extracellular Domain of the c- erbB-2 (HER-2/neu) Gene Product p185. In Press.

27. J. R. Wiener, K. Nakano, R. P. Kruzelock, C. Bucana, R.C. Bast, Jr., and G.E. Gallick. Decreased Src Tyrosine Kinase Activity Inhibits Malignant Human Ovarian Cancer Tumor Growth in a Nude Mouse Model. In Press.

1. J. R. Wiener, A. Berchuck, and R. C. Bast, Jr. Biology and Therapy with Biologic Agents in Gynecologic Cancer (Review). Curr. Opin. Oncol. 4:946-954, 1992.

2. R. Kruzelock, J. R. Wiener, and G. B. Mills. Human Cancer Genetics: Science Fiction Becomes Science Fact. Breast Diseases 8(1):15-19, 1997.

3. J. R. Wiener. Karate as a Beneficial Exercise for Human Health. Karate Connection. 2-4, October, 1998.

4. J. R. Wiener. Achilles Tendon Injuries. Karate Connection. In Press

1. R. C. Bast, Jr., J. Wiener, S. Kassim, S. Wu, C. Boyer, K. DeSombre, J. Hurteau, G. Rodriguez, G. Mills, A. Berchuck. Cell Growth Regulation in Ovarian Cancer: Tyrosine Kinases, Tyrosine Phosphatases, and Tumor Necrosis Factor-alpha. In: Ovarian Cancer 3. Eds. F Sharp, P Mason, J Berek. London: Chapman and Hall, pp 109-114, 1994.

2. G. B. Mills, S. Gibson, R. Schmandt, X.J. Fang, J. R. Wiener. Signal Transduction. In: Transplantation Biology. Eds NL Tilney, TB Strom, LC Paul. Philadelphia: Lippincott- Raven, pp 31-54, 1996.

3. R. C. Bast, Jr., F. Xu, Y. Yu, X. Fang, J. Wiener, G. B. Mills. Overview-The Molecular Biology of Ovarian Cancer. In: Ovarian Cancer 5. Eds. F Sharp, AD Blackett, JS Berek, RC Bast, Jr. Oxford: Isis Medical Media. Chapter 8, p87-97, 1998.

4. Y. Xu, X. Fang, T. Furui, T. Sasagawa, T. Pustilnik, Y. Lu, Z Shen, J. R. Wiener, L. Shayestek, J. W. Gray, R. C. Bast, Jr., G. B. Mills. Regulation of Growth of Ovarian Cancer Cells by Phospholipid Growth Factors. In: Ovarian Cancer 5. Eds. F Sharp, AD Blackett, JS Berek, RC Bast, Jr. Oxford: Isis Medical Media. Chapter 10, p109-120, 1998.

1. J. R. Wiener, R. Pal, Y. Barenholz, and R. R. Wagner. Influence of the Peripheral Matrix Protein of Vesicular Stomatitis Virus on the Membrane Dynamics of Mixed Phospholipid Vesicles: Fluorescence Studies. Federation of American Societies for Experimental Biology (FASEB). New Orleans, LA. 1982.

2. J. R. Wiener, J. A. Bartlett, and W. K. Joklik. Sequence of the M3 Gene of Reovirus Serotype 3. American Society for Virology (ASV). Santa Barbara, CA. 1986.

3. J. Bartlett, J. R. Wiener, and W. K. Joklik. Sequence of the L3 Gene of Reovirus Serotype 3 and an Analysis of the Protein that it Encodes. American Society for Virology (ASV). Chapel Hill, NC. 1987.

4. J. R. Wiener and W. K. Joklik. Sequences of the S3 Genes and M2 Genes of Reovirus Serotypes 1,2, and 3. American Society for Virology (ASV). Chapel Hill, NC. 1987.

5. W. K. Joklik, J. R. Wiener, J. A. Bartlett, and J. B. Antczak. The Structure and Function of Reovirus Genes. International Congress of Virology. Edmonton, Canada. 1987.

6. J. R. Wiener, T. McLaughlin, and W. K. Joklik. A Comparison of the L1 Genes of Reovirus Serotypes 1,2, and 3. American Society for Virology (ASV). Austin, TX. 1988.

7. C. Johnson, K. R. Kidd, J. R. Marks, J. D. Iglehart, and J. R. Wiener. Altered Expression of p53 Protein in Human Mammary Cell Lines. AOA Original Studies Symposium. Durham, NC. 1990.

8. K. R. Kidd, B. J. Kerns, and J. R. Wiener. An Improved Method for the Histochemical Analysis of Protein-Tyrosine Phosphatase Activity in Human Mammary Carcinomas. National Society for Histochemistry Symposium. San Antonio, TX. 1990.

9. S. Wu, C.M. Boyer, R. Whitaker, A. Berchuck, J. Wiener, J. B. Weinberg, and R. C. Bast, Jr. Induction of Tumor Necrosis Factor-alpha (TNF-alpha) in Human Ovarian Cancer Cells by Treatment with TNF-alpha and Interleukin-1-beta (IL-1-beta). American Association for Cancer Research (AACR). San Diego, CA. 1992.

10. R. C. Bast, Jr., C. M. Boyer, I. Jacobs, F. Xu, S. Wu, J. R. Wiener, and A. Berchuck. Cell Growth Regulation in Epithelial Ovarian Cancer. American Cancer Society (ACS). Orlando, FL. 1992.

11. C. M. Boyer, J. R. Wiener, F.J. Xu, G. S. Dean, B. S. Bast, K. C. O'Briant, M. J. Super, K. A. DeSombre, R. C. Bast Jr. Cytotoxicity of Immunotoxins Reactive with Different Epitop es on the c-erbB-2 (HER-2/neu) Gene Product, p185. American Association for Cancer Research (AACR). Orlando, FL. 1993.

12. J. R. Wiener, J. A. Hurteau, R. S. Whitaker, B. J. Kerns, A. Berchuck, R. C. Bast Jr. Overexpression of the Protein Tyrosine Phosphatase PTP1B in Human Ovarian Carcinomas. American Association for Cancer Research (AACR). Orlando, FL. 1993.

13. S. Wu, W. A. Meeker, J. Wiener, R. C. Bast Jr, C. M. Boyer. Transfection of Ovarian Cancer Cells with Tumor Necrosis Factor- (TNF-alpha) Antisense Abolishes the Proliferative Response to Interleukin-1 (IL-1) but not to TNF-alpha. American Association for Cancer Research (AACR). Orlando, FL. 1993.

14. R. C. Bast, Jr., J. R. Wiener, S. Wu, J.A. Hurteau, G. Rodriguez, M. Kohler, G. B. Mills, C. M. Boyer, A. Berchuck. Cell Growth Regulation of Epithelial Ovarian Cancer: The Potential Role of Tyrosine Phosphatases and Tumor Necrosis Factor-alpha (TNF- alpha). 4th Biennial Meeting of the International Gynecologic Cancer Society. Stockholm, Sweden. 1993.

15. J. R. Wiener, S. Kassim, A. Berchuck, R. C. Bast, Jr. Role of Protein Tyrosine Kinases and Protein Tyrosine Phosphatases in Human Ovarian and Mammary Cancer Cell Growth. 2nd International Symposium on Cancer Molecular Biology. Cairo, Egypt. 1993.

16. R. C. Bast, Jr., C. Boyer, F-J Xu, J. Wiener, S. Wu, R. Woolas, I. Jacobs, J. Hurteau, G. Mills, M. Kohler, A. Berchuck. Molecular Approaches to the Early Detection and Management of Ovarian Cancer. 2nd International Symposium on Cancer Molecular Biology. Cairo, Egypt. 1993.

17. J. Wiener, S. K. Kassim, A. Berchuck, R. C. Bast, Jr. Differential Expression of Protein Tyrosine Phosphatases in Human Ovarian Adenocarcinomas. American Association for Cancer Research (AACR). San Francisco, CA. 1994.

18. G. B. Mills, X. J. Fang, J. R. Wiener, F. Xu, Y. Yu, J. Wolf, D. Gershenson, J. T. Wharton, R. C. Bast, Jr. Molecular Mechanisms Regulating the Growth of Ovarian Cancer Cells: Potential Diagnostics and Targets for Therapy. 3rd International Symposium on Cancer Molecular Biology. Cairo, Egypt. 1995.

19. J. R. Wiener, R. P. Kruzelock, K. Nakayo, V. C. Estrella, G. B. Mills, R. C. Bast, Jr., and G. E. Gallick. Abrogation of Anchorage-Independent Growth of a HER-2- Overexpressing Malignant Human Ovarian Cancer Cell Line Transfected with an Antisense Expression Vector Specific for c-src. First Annual Meeting on the Experimental Therapeutics of Human Cancer. Hood College, MD. 1998.

20. C. G. Ioannides, A. Castilleja, B. Anderson, D. Kim, J. Wiener, and C.O'Brian. Post- translationally Enhanced Tumor Antigen Immunogenicity. Functional Antigenics Conference. Washington, D.C., 1998.

21. G. B. Mills, X. J. Fang, T. Furui, M. Mao, J. Wiener, V. Estrella, and Y. Xu. Lysophosphatidic Acid in Early diagnosis, Prognosis, and Therapy of Ovarian Cancer. First Annual International Conference on Ovarian Cancer. Houston, TX. 1999.

22. T. Pustilnik, V. Estrella, J. R. Wiener, and G. B. Mills. Lysophosphatidic Acid (LPA) 18:1 Stimulates Urokinase Secretion in Ovarian Cancer Cells. Society of Gynecologic Oncologists. San Francisco, CA. 1999.

NIH RO1 #1RO1 CA71418-01
Co-Principal Investigator - J. R. Weiner
Annual costs $126337 (9/96 - 9/97)
Grant duration:   9/96 -9/99

1. Ovarian Cancer Research Seminar Series, University of Texas, M.D. Anderson     Cancer Center, 1994 - 1996, Organizer.

2. Outreach Program, UTGSBS, Invited Speaker, Fort Bend County. July, 1997.

3. Long Distance Learning Program, UTGSBS, Invited Speaker. July, 1997.

4. Faculty Senate Representative, Department of Molecular Oncology, UT, M.D.     Anderson Cancer Center. September, 1997 - September, 1998.

5. Grant reviewer: M.D. Anderson Institutional Research Support Committee, 1997

6. Fort Bend County, TX Gifted and Talented Mentorship Program:
        Invited Panelist, October, 1997, and September, 1998
        Final Project Judge, May, 1998
        Fort Bend County Science Fair Program, Invited Speaker. March, 1998.

7. UTGSBS Academic Standards Committee, Alternate. 1998-1999.

8. Judge, Basic Sciences, M.D. Anderson Trainee Recognition Day, 1999.

1998      Guest Lecturer: Graduate Biochemistry, UTGSBS

1997      Invited Speaker: Long Distance Learning Program UT-GSBS

1996      Invited speaker: Pharmacology Graduate Seminar UT Medical School

1994 - 1995      Molecular Biology of Oncogenes, UTGSBS

1984 - 1988      Instructor Medical Virology / Microbiology Duke University                          Medical Center

1980      Instructor Medical Virology/Microbiology University of Virginia Medical               Center

1975 - 1979      Teaching Assistant
                         Department of Microbiology
                         University of Maryland
                         General Microbiology, Virology, Graduate Virology, and
                         Graduate Genetics