Gary S. Goldberg, Ph.D.

E-mail: garygoldberg@comcast.net
Phone: (856)566-6718
Office: Science Center B307
Department of Molecular Biology
UMDNJ-SOM
2 Medical Center Drive
Stratford, NJ 08084

Research

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. Ongoing projects include investigations of (1) Gap Junctional Communication, (2) other Intercellular Junctions, (3) Integrin Signaling, (4) Receptor Signaling, (5) Signal Transduction, and (6) Contact Normalization.

1. Gap Junctional Communication

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. These proteins combine 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. However, this research is pertinent to many other processes including anatomical morphogenesis, heart development, neuronal disorders, skin disease, and deafness.

2. other Intercellular Junctions

It has become clear that different types of intercellular junctions interact with each other to control many facets of cell growth and behavior. We are investigating mechanisms by which cadherins interact with integrins and other cellular structures to affect cell growth and migration. This work is designed to elucidate novel reagents and protocols to combat several kinds of cancer.

3. Integrin Signaling

In general, nontransformed cells are anchorage independent, and can only survive and proliferate in the appropriate microenvironment. In contrast, most cancer cells overcome this dependency to become capable of nonanchored growth and migration. These hallmarks of transformed cell growth underlie the ability of cancer cells to become malignant and metastatic. We are currently elucidating mechanisms by which integrins interact with other proteins, including signal transduction kinases and cytoskeletal components, to control these events. These studies are designed to understand fundamental processes that differentiate cancer cells from their nontransformed precursors.

4. Receptor Signaling

In addition to intercellular junctions, cell growth and behavior can be controlled by diffusible factors. We are currently identifying novel factors that control tumor cell growth. This work should lead to innovative ways to detect and treat many kinds of cancer.

5. Signal Transduction

Ultimately, extracellular signals transmitted by junctional contact or diffusible factors must be transduced inside the cell to exert measurable effects. We are performing global, comprehensive, and nonbiased analyses to understand how this occurs. These studies are identifying novel tumor suppressor genes, as well as genes that promote nonanchored cell growth and migration. Results from this work is leading to the development of new biomarkers to detect specific types of caner, as well as reagents that may be used to suppress cancer progression.

6. Contact Normalization

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 specifically block cancer cell growth without harming other cells in the body.

Selected peer-reviewed publications since 1996

•  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.

•  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.

•  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.

•  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.

•  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.

•  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.

•  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.

•  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.

•  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 .

•  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.

•  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 .

•  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.

•  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.

•  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 .

•  Goldberg, G.S. , Valiunas, V., and Brink, P.R. (2004) Selective permeability of gap junction channels. Biochimica et Biophysica Acta 1662, 96-101.

•  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.

•  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.

•  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 .

•  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.

• 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.

• 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.

• 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 .

•  Goldberg, G.S. (in press) Contact Normalization. In: Schwab , M.E. (Eds.) Encyclopedia of Cancer. Heidelberg : Spinger-Verlag.

•  Goldberg, G.S. (in press) Gap Junctions. In: Schwab , M.E. (Eds.) Encyclopedia of Cancer. Heidelberg : Spinger-Verlag.

•  Pahujaa, M., Anikin, M., and Goldberg, G.S. (in press) Phosphorylation of Connexin43 induced by Src: regulation of gap junctional communication between transformed cells. Experimental Cell Research.