Molecular Biology

Faculty and Research Interests

Gary Goldberg, PhDGary S. Goldberg, PhD

Associate Professor
Science Center B307
856 566-6718
garygoldberg@comcast.net

Education

West Virginia University, WV
PhD (Genetics and Developmental Biology) , 1990

University of Georgia , GA
BS (Biology and Genetics) , 1983

Research Interests

Cells must communicate with each other to coordinate the development and survival of an animal. This communication can be mediated by diffusible factors that pass between cells, or by direct contact through cell junctions. I am interested in how intercellular communication affects cell growth and differentiation, with an emphasis on how cell communication can control tumor cell growth, invasion, and metastasis, as well as eye development and cataract formation.

Connexins are integral membrane proteins which have evolved into a family of over 20 mammalian members that are most commonly referred to by their molecular weights. Connexins associate with each other to produce channels that directly connect the cytoplasm of adjacent cells. These channels, called gap junctions, enable cells to communicate with each other by sharing hydrophilic molecules of up to around 1 kD in size. Gap junctional communication is necessary for healthy development and homeostasis. Abnormal connexin phenotypes can result in several diseases. Therefore, it is important to understand how cells communicate with each other by gap junctions. We are studying how gap junctional communication is controlled, and the signals that pass between cells through gap junctions. Our experimental systems are geared to investigate lens development, cataracts, and cancer. For example, as shown in Figure 1, we are in the process of identifying molecules that travel between cells through channels formed by Cx43, Cx46, and Cx50 that promote proper lens development and prevent cataract formation. However, this research is pertinent to many other processes including anatomical morphogenesis, heart development, neuronal disorders, skin disease, and deafness.

Figure 1: Differential transfer of signaling molecules through lens connexins. Cx43, Cx46, and Cx50 are predominant connexins expressed in the lens. Studies from connexin knockout mice and human mutations indicate that Cx46 and Cx50 can both mediate the intercellular transfer of molecules that prevent cataract formation, while Cx50 forms channels that are uniquely required for lens epithelial cell proliferation. We are currently analyzing the transfer of endogenous molecules that travel through channels formed by these connexins between cells.

Intercellular junctions mediate signals that allow normal cells to inhibit the transformed growth of neighboring tumor cells. The process is called “Contact Normalization”. Intimate junctional contact between tumor cells and normal cells is needed for this form of growth control. We are defining the role of cell junctions, including connexins, integrins, and cadherins, in this phenomenon. The long term goals of this work are to identify tumor markers and chemotherapeutic targets, and to develop agents that effectively block cancer cell growth without harming other cells in the body. For example, as shown in Figure 2, we have identified reagents that specifically inhibit pathways required for nonanchored tumor cell growth, migration, and survival.

Figure 2: Contact normalization and neutralization of tumor cell growth. The Src kinase phosphorylates Cas, which associates with Cx43 and Crk to block gap junctional communication and promote nonanchored cell growth and migration. However, cancer cell growth can be controlled by surrounding nontransformed cells. We have found specific growth factor receptors, adaptor proteins, and other signaling molecules, including miRNA, that promote (red) or inhibit (blue) this process. These molecules can be used as biomarkers to detect cancer, as well as targets to neutralize malignant and metastatic cancer cells. For example, we have identified kinase blockers, siRNA molecules, antisera, and competitive receptor ligands (green) that can synergistically suppress coordinated pathways that are required for tumor cell survival and invasion.

Contribute to Cancer Research Project

A major problem with most current cancer treatments lies in their toxic effects on other cells in the body. Thus, chemotherapy often makes patients sick. Indeed, in some cases, it is not known if a patient actually dies from cancer rather than the treatment they undergo to combat it. However, nature has evolved a way to fight cancer without harming other cell in the body. This method is called, “contact normalization”.

Contact normalization describes the ability of nontransformed cells to normalize the growth of neighboring cancer cells. This is a very wide spread and powerful phenomenon. Tumor cells need to overcome this form of growth inhibition before they can become malignant or metastatic.

We have performed comprehensive analysis to identify genes that are affected during contact normalization. We found that expression of specific genes are activated in transformed cells, but suppressed in nontransformed cells. We also found that expression of these genes is inhibited in transformed cells that are undergoing contact normalization.

Four of these genes are, to the best of our knowledge, not yet described in the literature or any domain. It should be noted that our procedures enabled us to identify these genes as prime candidates for biomarkers and chemotherapy targets from a list comprising over 39 thousand mRNA transcripts (potentially representing every gene in the cell). At least one of these genes encodes an integral membrane protein with an extracellular domain. Therefore, this protein may be readily used to target cancer cells in patients. In fact, we have identified compounds that can bind to this receptor and block tumor cell migration. 

Thus, these genes can be used in a few ways: (1) as accurate biomarkers to detect cancer; (2) as prognostic indicators to determine the invasive and metastatic potential of cancer cells; and (3) as chemotherapeutic targets to specifically block malignant cancer cell invasion and neutralize their metastatic growth potential by application of nontoxic compounds. It should be stressed that these protocols are highly specific for malignant and metastatic cancer cells; they should not significantly interfere with other noncancerous cells in the adult body.

The Foundation of UMDNJ has established a fund where 100% of donated money will go directly to this research program with no administrative or other deductions. To support the "Goldberg Cancer Research Program" with your charitable contribution, contact Gary Goldberg at (856) 566-6718 or at gary.goldberg@umdnj.edu. You may also mail your check, made payable to the "Foundation of UMDNJ", to the Gary Goldberg, Molecular Biology, Science Center, Two Medical Center Drive, UMDNJ, Stratford, NJ 08084. Please add "Goldberg Cancer Research" to the memo portion of your check.

Recent Publications

  1. Goldberg, G.S. and Kaczmarczyk, W. (1993) A chicken genomic DNA fragment that hybridizes to the murine Hox-3.1 homeobox is likely to encode the NADH ubiquinone oxidoreductase subunit B15. Gene 133, 233-235.
  2. Goldberg, G.S. and Kaczmarczyk, W. (1992) Sequence of a novel chicken genomic DNA fragment that hybridizes to the murine Hox-3.1 homeobox. Gene 121, 397-398.
  3. Gu, J., Yassini, P., Goldberg, G., Zhu, W., Konat, G., and Wiggins, R.C. (1993) Cocaine cytotoxicity in serum-free environment: C6 glioma cell culture. NeuroToxicology 14, 19-22.
  4. Goldberg, G.S. and Lau, A.F. (1993) Dynamics of Cx43 phosphorylation in pp60 v-src -transformed cells. Biochemical Journal 295, 735-742.
  5. Goldberg, G.S. and Lau, A.F. (1993) Transfection of mammalian cells with PEG purified plasmid DNA. BioTechniques 14, 548-549.
  6. Goldberg, G.S., Martyn, K.D., and Lau, A.F. (1994) A connexin43 antisense vector reduces the ability of normal cells to inhibit the foci formation of transformed cells. Molecular Carcinogenesis 11, 106-114.
  7. Goldberg, G.S. and Bertram, J.S. (1994) Retinoids, gap junctional communication, and suppression of epithelial tumors. In Vivo 8, 745-754.
  8. Goldberg, G.S. and Bertram, J.S. (1994) In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Research 54, 3947-3948.
  9. Gibson, D.F., Hossain, M.Z., Goldberg, G.S., Acevedo, P., and Bertram, J.S. (1994) The mitogenic effects of transforming growth factors b 1 and b 2 in C3H/10T1/2 cells occur in the presence of enhanced gap junctional communication. Cell Growth and Differentiation 5, 687-696.
  10. Goldberg, G.S., Bechberger, J.F., and Naus, C.C.G. (1995) A preloading method of evaluating gap junctional communication by fluorescent dye transfer. Biotechniques 18, 490-497 .
  11. Li, H., Liu, T.-F., Lazrak, A., Peracchia, C., Goldberg, G.S. , Lampe, P.D., and Johnson, R. (1996) Properties and regulation of gap junctional hemichannels in the plasma membranes of cultured cells. Journal of Cell Biology 134, 1019-1030.
  12. Orlando-Mathur, C.E., Bechberger, J.F., Goldberg, G.S. , Naus, C.C.G., Kidder, G.M., and Kennedy, T.G. (1996) Rat endometrial stromal cells express the gap junction genes connexin26 and 43 and form functional gap junctions during in vitro decidualization. Biology of Reproduction 54, 905-913.
  13. Goldberg, G.S. , Moreno , A.P., Bechberger, J.F., Hearn, S., Shivers, R.R., MacPhee, D.J., Zhang, Y.-C., and Naus, C.C.G. (1996) Evidence that disruption of connexon particle arrangements in gap junction plaques is associated with inhibition of gap junctional communication by a glycyrrhetinic acid derivative. Experimental Cell Research 222, 48-53.
  14. Gibson, D.F.C., Bikle, D.D., Harris, J., and Goldberg, G.S. (1997) The expression of the gap junctional protein Cx43 is restricted to proliferating and non-differentiated normal and transformed keratinocytes. Experimental Dermatology 6, 167-174.
  15. Goldberg, G.S. and Moreno , A.P. (1998) Inhibition of connexin43 junctional conductance by 2,3-butanedione monoxime (BDM). In: Werner, R. (Ed.) Gap junctions , pp. 210-214. Amsterdam : IOS Press.
  16. Goldberg, G.S. , Lampe, P.D., Sheedy, D., Stewart, C.C., Nicholson, B.J., and Naus, C.C.G. (1998) Direct identification and analysis of transjunctional ADP from Cx43 transfected C6 glioma cells. Experimental Cell Research 239, 82-92.
  17. Goldberg, G.S. , Lampe, P.D., and Nicholson, B.J. (1999) Selective transfer of endogenous metabolites through gap junctions composed of different connexins. Nature Cell Biology 1, 457-459.
  18. Nicholson, B.J., Weber, P.A., Cao, F., Chang, H-C., Lampe, P.D., and Goldberg, G.S. (1999) The molecular basis of selective permeability of connexins is complex and includes both size and charge. Brazilian Journal of Medical and Biological Research 33, 369-378.
  19. Goldberg, G.S. , Bechberger, J.F., Tajima, Y., Merritt, M., Omori, Y., Gawinowicz, M.A., Narayanan, R., Tan, Y., Sanai, Y., Yamasaki, H., Naus, C.C.G., Tsuda, H., and Nicholson, B.J. (2000) Connexin43 suppresses MFG-E8 while inducing contact growth inhibition of glioma cells. Cancer Research 60, 6018-6026 .
  20. Goldberg, G.S. and Lampe, P.D. (2001) Capture of endogenous transjunctional metabolites. In: Bruzzone R. and Giaume C. (Eds.) Methods in Molecular Biology: Connexin Channels Methods and Protocols , pp. 329-340. Totowa NJ : Humana Press, Inc.
  21. Goldberg, G.S. , Jin, Z., Ichikawa, H., Naito, A., Ohki, M., El-Deiry, W., and Tsuda, H. (2001) Global effects of anchorage on gene expression during mammary carcinoma cell growth reveal role of tumor necrosis factor-related apoptosis inducing ligand in anoikis. Cancer Research 61, 1334-1337 .
  22. Goldberg, G.S., Moreno , A.P., and Lampe, P.D. (2002) Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP. Journal of Biological Chemistry 277, 36725-36730.
  23. Alexander, D.B. and Goldberg, G.S. (2003) Transfer of biologically important molecules between cells through gap junction channels. Current Medicinal Chemistry 10, 2045-2058.
  24. Goldberg, G.S., Alexander, D.B., Pellicena, P., Zhang, Z.-Y., Tsuda, H., and Miller, W.T. (2003) Src phosphorylates Cas on tyrosine 253 to promote migration of transformed cells. Journal of Biological Chemistry 278, 46533-46540 .
  25. Goldberg, G.S. , Valiunas, V., and Brink, P.R. (2004) Selective permeability of gap junction channels. Biochimica et Biophysica Acta 1662, 96-101.
  26. Alexander, D.B., Ichikawa, H., Bechberger, J.F., Valiunas, V., Ohki, M., Naus, C.C.G., Kunimoto, T., Tsuda, H., Miller, W.T., and Goldberg, G.S. (2004) Normal cells control the growth of neighboring transformed cells independent of gap junctional communication and Src activity. Cancer Research 64, 1347-1358.
  27. Goldberg, G.S., Kunimoto, T., Alexander, D.B., Suenaga, K., Ishidate, F., Miyamoto, K., Ushijima, T., Teng, C.T., Yokota, J., Ohta, T., Tsuda, H. (2005) Full length and delta lactoferrin display differential cell localization dynamics, but do not act as tumor markers or significantly affect the expression of other genes. Medicinal Chemistry 1, 57-64.
  28. Valiunas, V., Bechberger, J.F., Naus, C.C.G., Brink, P.R., and Goldberg, G.S. (2005) Nontransformed cells can normalize gap junctional communication with transformed cells. Biochemical and Biophysical Research Communications 333, 174-179 .
  29. Naus, C.C., Goldberg, G.S., and Sin, W.C. (2005) Connexins in growth control and cancer. In: Winterhager, E.. (Eds.) Gap junctions in development and disease. pp. 253-265. New York : Spinger-Verlag.
  30. Shen, Y., Jia Z., Nagele R.G., Ichikawa H., and Goldberg G.S. (2006) Src utilizes Cas to suppress Fhl1 in order to promote nonanchored growth and migration of tumor cells. Cancer Research 66, 1543-1552.
  31. Patwardhan, P., Shen, Y., Goldberg, G.S. , and Miller, W.T. (2006) Individual Cas phosphorylation sites are dispensable for processive phosphorylation by Src and cellular transformation. Journal of Biological Chemistry 281, 20689-20697.
  32. Shen, Y., Khusial, P.R., Li, X., Ichikawa , H., Moreno , A.P., and Goldberg, G.S. (2007) Src utilizes Cas to block gap junctional communication mediated by connexin43. Journal of Biological Chemistry 282, 18914-18921 .
  33. Pahujaa, M., Anikin, M., and Goldberg, G.S. (2007) Phosphorylation of Connexin43 induced by Src: regulation of gap junctional communication between transformed cells. Experimental Cell Research 313, 4083–4090.
  34. Li, X., Jia, Z., Shen, Y., Ichikawa, H., Jarvik, J., Nagele, R.J., and Goldberg, G.S. (2008) Coordinate suppression of Sdpr and Fhl1 expression in tumors of the breast, kidney, and prostate. Cancer Science 99, 1326-1333.
  35. Goldberg, G.S. (in press) Contact Normalization. In: Schwab , M.E. (Eds.) Encyclopedia of Cancer. Heidelberg : Spinger-Verlag.
  36. Goldberg, G.S. (in press) Gap Junctions. In: Schwab , M.E. (Eds.) Encyclopedia of Cancer. Heidelberg : Spinger-Verlag.

 

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