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The isoprene compounds, farnesyl pyrophosphate and
geranyl pyrophosphate, are intermediates in the cholesterol biosynthetic
pathway and are derived from mevalonic acid. Impairment of mevalonic
acid biosynthesis by inhibition of hydroxymethylglutaryl coenzyme A
(HMG CoA) reductase activity profoundly alters the proliferative and
differentiation characteristics of a wide variety of normal and malignant
mammalian cell types. Many intracellular proteins, such as those derived
from the RAS and RAS-related oncogene families, that regulate proliferation
and differentiation are covalently linked to either farnesyl pyrophosphate
or geranylgeranyl pyrophosphate. For many of these proteins, isoprenylation
is essential for normal regulating activities.
 Our
laboratory is investigating the hypothesis that depletion of isoprene
compounds by HMG CoA reductase inhibition alters cell proliferation
and differentiation primarily because of changes in the intracellular
function of isoprenylated regulating proteins. We are also developing
inhibitors of farnesyl protein transferase that mediates farnesylation
of RAS and related proteins as well as other enzymes in this pathway.
Specific research projects:
1) |
Studying the use of
HMG CoA reductase inhibitors alone and in combination with standard
chemotherapeutic agents to alter human malignant cell proliferation
as well as the use of these agents to alter the differentiation of both
normal human leukocytes and leukemia cells. |
2) |
Determining the effects of
selective inhibitors of protein isoprenylation reactions on levels
and functional activities of isoprenylated regulatory proteins, such
as those of the RAS oncogene family. |
3) |
(a) Understanding differences
in the clinical pharmacology of the HMG CoA reductase inhibitors in
normal volunteers and in patients with malignancies, and (b) determining
whether HMG CoA reductase inhibition alters the toxicology profiles
of standard chemotherapeutic agents. |
| 4) |
(a) Assessing the role of membrane
composition (cholesterol and saturated/polyunsaturated fatty acid
content) on the membrane association of isoprenylated proteins, and
(b) specific pharmacologic agents that modify both membrane content
and isoprenylated protein activities are examined. |
Representative Publications:
Dudakovic, A., Wiemer, A.J., Lamb, K.M., Vonnahme, L.A., Dietz, S., Hohl, R.J.: Inhibition of Geranylgeranyl Diphosphate Synthase Induces Apoptosis through Multiple Mechanisms and Displays Synergy with Inhibition of Other Isoprenoid Biosynthetic Enzymes. J of Pharmacol and Experi Therap 324:1028-1036, 2008.
Hamadmad, S.N., Hohl, R.J.: Erythropoietin Stimulates Cancer Cell Migration and Activates RhoA Protein through a MAPK/Erk-Dependent Mechanism. J of Pharmacol and Experi Therap 324:1227-1233, 2008.
Hamadmad, S.N., Hohl, R.J.: Lovastatin Suppresses Erythropoietin Receptor Surface Expression through Dual Inhibition of Glycosylation and Geranylgeranylation. Biochemical Pharmacology 74(14):590-600, 2007.
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here to see a list of additional publications
Center and Program
affiliations:
Holden Comprehensive Cancer Center
The
Medical Scientist Training Program
Biosciences
Program |
