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SONDRA BERGER Lab
LAB PERSONNEL
Sondra Berger, Ph.D. Associate Professor, USC
PUBLICATIONS
The enzyme thymidylate synthase (TS) is a
target of 5-fluoropyrimidine (FP) drugs utilized in the
treatment of breast, gastrointestinal tract, and head and
neck cancers. Naturally-occurring variation in TS has been
observed in human tumors and tumor cell lines. In one human
colorectal tumor cell line, a structural alteration in TS
has been identified that confers resistance to FP drugs.
Thus, variations in TS structure among human tumors may play
an important role in tumor response to FP therapy. With a
long-term goal of improving the therapeutic outcome in
cancer, the Berger laboratory is collaborating with a group
of basic and clinical scientists:
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to determine whether functional
variation in TS occurs in colon tumors.
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to identify the structural basis for
TS functional variation.
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to correlate the relationships
between TS expression and tumor response to chemotherapy
directed at TS.
The identification of structural
alteration in TS in human tumors can lead to the development
of markers that are useful for screening tumors for TS
variation. Ultimately, these studies may lead to the
prediction of tumor response prior to chemotherapy. This
increases the likelihood that the patient will receive
therapy of benefit against the tumor. In addition to the
fluoropyrimidines, numerous chemical agents have been
synthesized as potential inhibitors of TS. With the
resolution of the three dimensional structures of TSs by
Xray crystallography, novel agents are being designed by
computer- assisted approaches.
A major structural feature of TSs is a
discontinuity in several -sheets that form the central core
of the protein. It is proposed that this discontinuity
serves as a hinge to facilitate the movement of the residues
of the protein toward the active site during catalysis. The
Berger laboratory is investigating the chemical and physical
characteristics that stabilize this region. Residues that
are located at the bulge in one of the -sheets are being
replaced by the use of site- directed mutagenesis. By
analyzing the effect of residue substitution on TS function,
it may be possible to design chemical agents that can
perturb this region.
Li L, Berger SH, Wyatt MD. Involvement of
base excision repair in response to therapy targeted at
thymidylate synthase. Mol Cancer Ther. 2004 Jun;3(6):747-53.
Berger SH, Berger FG, Lebioda L. Effects
of ligand binding and conformational switching on
intracellular stability of human thymidylate synthase.
Biochim Biophys Acta. 2004 Jan 14;1696(1):15-22.
Berger, S.H., Barbour, K.W., Berger F.G.,
A Naturally Occurring Variation in Thymidylate Synthase
Structure is Associated with a Reduced Response to
5-Fluoro-2'-deoxyuridine in a Human Colon Tumor Cell Line,
Mol. Pharmacol., 34, 480-484 (1988).
Yousef AM, Davis RA, Sticca RP, Berger SH.
Structural analysis of cDNA encoding thymidylate synthase in
hepatic metastases of human colorectal tumors. Int J
Colorectal Dis. 2001 Sep;16(5):318-25.
Phan J, Koli S, Minor W, Dunlap RB,
Berger SH, Lebioda L. Human thymidylate synthase is in the
closed conformation when complexed with dUMP and raltitrexed,
an antifolate drug. Biochemistry. 2001 Feb
20;40(7):1897-902.
Phan J, Steadman DJ, Koli S, Ding WC,
Minor W, Dunlap RB, Berger SH, Lebioda L. Structure of human
thymidylate synthase suggests advantages of chemotherapy
with noncompetitive inhibitors. J Biol Chem. 2001 Apr
27;276(17):14170-7. Epub 2001 Jan 24.
Hoganson DK, Williams AW, Berger SH.
Isolation and characterization of a thymidylate synthase-deficient
human colon tumor cell line. Biochem Pharmacol. 1999 Nov
15;58(10):1529-37.
Zapf JW, Zhao PS, Steadman DJ, Berger SH.
Genetic complementation and resistance to
5-fluoro-2'-deoxyuridine in thymidine auxotrophs expressing
a highly defective mutant of human thymidylate synthase.
Biochem Pharmacol. 1999 Sep 15;58(6):973-81.
Steadman DJ, Spencer HT, Dunlap RB,
Berger SH. Substitution at residue 214 of human thymidylate
synthase alters nucleotide binding and isomerization of
ligand-protein complexes. Biochemistry. 1999 Apr
27;38(17):5582-7.
Williams AW, Dunlap RB, Berger SH. A hydroxyl group at
residue 216 is essential for catalysis by human thymidylate
synthase. Biochemistry. 1998 May 19;37(20):7096-102.
Steadman DJ, Zhao PS, Spencer HT, Dunlap RB, Berger SH. A
structural role for glutamine 214 in human thymidylate
synthase. Biochemistry. 1998 May 19;37(20):7089-95.
Hughey CT, Barbour KW, Berger FG, Berger SH. Functional
effects of a naturally occurring amino acid substitution in
human thymidylate synthase. Mol Pharmacol. 1993
Aug;44(2):316-23.
Davis ST, Berger SH. Variation in human thymidylate synthase
is associated with resistance to 5-fluoro-2'-deoxyuridine.
Mol Pharmacol. 1993 May;43(5):702-8.
Hughey CT, Barbour KW, Berger FG, Berger SH. Genetic
variation in thymidylate synthase confers resistance to
5-fluorodeoxyuridine. Adv Exp Med Biol. 1993;339:67-76.
Hughey, C.T., Barbour, K.W., Berger, F.G., and Berger, S.H.,
Functional Effects of a Naturally Occurring Amino Acid
Substitution in Human Thymidylate Synthase, Mol. Pharmacol.
44, 316-323 (1993).
Barbour KW, Hoganson DK, Berger SH, Berger FG. A naturally
occurring tyrosine to histidine replacement at residue 33 of
human thymidylate synthase confers resistance to
5-fluoro-2'-deoxyuridine in mammalian and bacterial cells.
Mol Pharmacol. 1992 Aug;42(2):242-8.
Berger SH, Hakala MT. Calcium leucovorin and 5-fluorouridine
cytotoxicity. J S C Med Assoc. 1990 May;86(5):284-9. Erratum
in: J S C Med Assoc 1990 Sep;86(9):517.
Barbour KW, Berger SH, Berger FG. Single amino acid
substitution defines a naturally occurring genetic variant
of human thymidylate synthase. Mol Pharmacol. 1990
Apr;37(4):515-8.
Davis ST, Berger SH. Modulation of 5-fluoro-2'-deoxyuridine
response by folinic acid in human colonic tumor cell lines:
the role of thymidylate synthase. Mol Pharmacol. 1989
Apr;35(4):422-7.
Berger SH, Barbour KW, Berger FG. A naturally occurring
variation in thymidylate synthase structure is associated
with a reduced response to 5-fluoro-2'-deoxyuridine in a
human colon tumor cell line. Mol Pharmacol. 1988
Oct;34(4):480-4.
Berger SH, Berger FG. Thymidylate synthase as a determinant
of 5-fluoro-2'-deoxyuridine response in human colonic tumor
cell lines. Mol Pharmacol. 1988 Oct;34(4):474-9.
Barbour KW, Berger SH, Berger FG, Thompson EA Jr.
Glucocorticoid regulation of the genes encoding thymidine
kinase, thymidylate synthase, and ornithine decarboxylase in
P1798 cells. Mol Endocrinol. 1988 Jan;2(1):78-84.
Berger SH, Davis ST, Barbour KW, Berger FG. The role of
thymidylate synthase in the response to
fluoropyrimidine-folinic acid combinations. Adv Exp Med
Biol. 1988;244:59-69.
Clark JL, Berger SH, Mittelman A, Berger FG. Thymidylate
synthase gene amplification in a colon tumor resistant to
fluoropyrimidine chemotherapy. Cancer Treat Rep. 1987
Mar;71(3):261-5.
Berger SH, Jenh CH, Johnson LF, Berger FG. Thymidylate
synthase overproduction and gene amplification in
fluorodeoxyuridine-resistant human cells. Mol Pharmacol.
1985 Nov;28(5):461-7.
Berger SH, Hakala MT. Relationship of dUMP and free FdUMP
pools to inhibition of thymidylate synthase by
5-fluorouracil. Mol Pharmacol. 1984 Mar;25(2):303-9.
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