Joseph Landolph Associate Professor Research Interests
Molecular Biology of Chemical Carcinogenesis Induced by Nickel and Chromium Compounds
Our laboratory uses the techniques of molecular biology
to study the molecular and cellular mechanisms of
chemical carcinogenesis. We are utilizing model cell
culture systems to study the molecular and cellular
mechanisms of chemically induced morphological and
neoplastic transformation. Specifically, we are studying
the processes of oncogene activation and tumor
suppressor gene inactivation in chemically induced
neoplastic cell transformation.
First, epidemiological studies have shown that exposure
of workers in specific nickel refinery operations to
sulfidic and oxidic nickel-containing ores, containing
mixtures of soluble and insoluble nickel compounds,
correlates with increased incidence of nasal and
respiratory cancer. Specific insoluble nickel
compounds, such as nickel subsulfide and nickel oxide,
are carcinogenic when administered to rats by
inhalation, but soluble nickel sulfate is not carcinogenic
by inhalation.
We are studying the molecular and cellular mechanisms
of induction of morphological and neoplastic
transformation of C3H/10T1/2 Cl 8 mouse embryo
cells by specific insoluble carcinogenic nickel
compounds as a model for nickel compound
carcinogenesis and by specific chromium compounds as
a model for chromium carcinogenesis. We found that
insoluble nickel compounds, including nickel subsulfide,
nickel oxides, and anhydrous nickel sulfate are taken up
into C3H/10T1/2 mouse embryo cells by phagocytosis,
and induce cytotoxicity, chromosome aberrations, and
morphological transformation in 10T1/2 cells. The
morphologically transformed foci form transformed cell
lines that form stable foci, grow in soft agar, and some
form tumors when injected into nude mice. The ability of
the insoluble nickel compounds to be phagocytosed
correlates with their ability to induce morphological
transformation, indicating cellular uptake of these
insoluble nickel compounds is one step in the process of
morphological transformation, likely because
phagocytosis leads to a high concentration of
intracellular nickel ions.
Next, we have used the technique of mRNA differential
display to determine which genes are over-expressed
and which genes are under-expressed in nickel
compound-induced, transformed 10T1/2 cell lines.
Results to date indicate that 130 genes are
under-expressed or over-expressed in the transformed
cell lines. We have identififed and are studying ten of
these genes. We have found that the ect-2
proto-oncogene, the Wdr-1 stress response gene, and
the calnexin chaperone gene are expressed at higher
steady-state levels in the transformed cell lines. The
ect-2 oncogene is expressed at high steady-state levels
at the protein level, and it is also amplified in nickel
transformed 10T1/2 cell lines. We have also found that
the DRIP/TRAP-80 gene, the IGF-1 receptor encoding
gene, and two novel genes have their expression
abolished in the transformed cell lines. We are currently
testing the hypothesis that activation of and
over-expression of the ect-2 proto-oncogene, the
Wdr-1 gene, and the calnexin gene, and inhibition of
expression of the DRIP/TRAP-80 gene, the IGF-1
receptor encoding gene, and the two novel genes
contribute to the induction and maintenance of the
transformed phenotype induced by carcinogenic
insoluble nickel compounds in 10T1/2 cells.
A second project in our laboratory insolves the fact that
workers in the chromate-producing industries and in in
the chrome-plating industries have higher incidences of
nasal and respiratory cancers. Many insoluble and
soluble chromium compounds are carcinogenic in
animals. We have shown that lead chromate induces
morphological transformation in 10T1/2 mouse embryo
cells, providing a model cell culture system in which to
study chromium-induced cell transformation. We are
now investigating the spectrum of compounds containing
hexavalent chromium compounds that induce
morpholgical cell transformation, the role of pentavalent
chromium compounds in chromate carcinogenesis, and
the role of trivalent chromium compounds, particularly
insoluble trivalent chromium compounds, in chormate
carcinogenesis. We are int he process of using mRNA
differential display and DNA microarrays to investigate
aberrations in gene expression in chromate transformed
10T1/2 cell lines.
Dr. Landolph is a member of the Carginogen
Identification Committee which reports to the Scientific
Advisory Board of the Office of Environmental Health
and Assessment of the California E.P.A. He was
appointed by the successive Governors of California to
this position. Dr. Landolph has also been appointed as a
member of the Scientific Advisory Board of the U.S.
Environmental Protection Agency for the period
2002-2004.
Degrees
UC - Berkeley, PHD, 1976
Huang, N., Cerapnalkoski, L., Nwankwo, J., Dews, M. L., and Landolph, J. R. Induction of Chromosomal Aberrations, Cytotoxicity, and Morphological Transformation in Mammalian Cells by the Antiparasitic Drug, Flubendazole, and by the Anti-Neoplastic Drug, Harringtonine. Fundamental Applied Toxicology. 22: 304-313, l994.
Landolph, J. R., Dews, M., Ozbun, L., and Evans, D. Metal-Induce Gene Expression and Neoplastic Transformation. In: Toxicology of Metals, Part I. General and Clinical Aspects, Risk Assessment, and Genotoxicity of Metals. Ed. L. W. Chang. CRC Press, Lewis Publishers, Inc., Boca Raton, Florida, pp. 321-329, l996.
Landolph, J. R. Role of Free Radicals in Metal-Induced Carcinogenesis. In: Metal Ions in Biological Systems: Interrelations Between Free Radicals and Metal Ions in Life Processes. Eds. A. Sigel and H. Sigel. pp. 445-483, l999.
Landolph, J. R. The Role of Free Radicals in Chemical Carcinogenesis. In: Toxicology of the Human Environment: The Critical Role of Free Radicals. Ed. C. J. Rhodes. Taylor and Francis Series in Pharmaceutical Sciences, pp. 339-362, 2000.
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