|
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, invasion, and metastasis. 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
2.
Other Intercellular Junctions
3.
Integrin Signaling
4,
Receptor Signaling
5.
Signal Transduction
6.
Contact Normalization
Peer-Reviewed
Publications
Contribute
to Cancer Research Project
 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. 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. 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 develop 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 are leading to
the development of new biomarkers to detect specific types of cancer,
as well as reagents that may be used to stop 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.
 
Peer-Reviewed Publications
•
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.
•
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.
•
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.
•
Goldberg, G.S.
and Lau, A.F. (1993) Dynamics of Cx43 phosphorylation in pp60 v-src
-transformed cells. Biochemical Journal 295, 735-742.
•
Goldberg, G.S.
and Lau, A.F. (1993) Transfection of mammalian cells with PEG purified
plasmid DNA. BioTechniques 14, 548-549.
•
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.
•
Goldberg, G.S.
and Bertram, J.S. (1994) Retinoids, gap junctional communication,
and suppression of epithelial tumors. In
Vivo 8, 745-754.
•
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.
•
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.
•
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 .
•
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 .
•
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.
• 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.
•
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.
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
Research 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 contribute to this project,
please send a check made payable to the UMDNJ Research Foundation
with the memorandum “Goldberg Cancer Research” to:
Farah
Stith
Vice
President
Research
Foundation of UMDNJ
146
Academic Center
1
Medical Center Drive
Stratford
, NJ 08084
856-566-5072
stithfa@umdnj.edu
|
