Vanderbilt-Ingram Cancer Center

The VICC.ORG Investigator Directory

Michael L. Freeman, Ph.D.

Professor
VICC Member
Researcher

Vanderbilt-Ingram Cancer Center Radiation Oncology
22nd at Pierce Avenue, B1034
Nashville, TN 37232-5671
Phone: 615-322-2555
Fax: 615-343-3075

Contact Information:

Vanderbilt Department of Radiation Oncology
Medical Center North, E-1200
Nashville, TN 37232
615-322-3606

Research Description:

The Freeman laboratory focuses on two aspects of cancer drug development: 1) Development of efficacious sensitizers of ionizing radiation . 2-Indol-3-yl-methylenequinuclidin-3-ols are being used as the basis for development of novel radiation sensitizers. Defined DNA substrates, cell and animals models are used in the approach to design specific sensitizers. 2) Providing a rationale basis for development of chemoprevention agents. Expression of the genes that encode Phase II detoxification proteins is regulated by the transcription factor Nrf2,which itself is negatively regulated by association to the Cul-3 ubiquitin ligase adaptor protein Keap1. Proteomics, biochemical, biophysical and genetic approaches are used to determine if Keap1's activity is regulated by multiple Cys residues that exhibit differential chemical reactivity, allowing integration of different chemical input signals.

Publications:

• Sekhar, KR, Rachakonda, G, Freeman, ML Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicol Appl Pharmacol, 244(1), 21-6, 2010.
• Rachakonda, G, Sekhar, KR, Jowhar, D, Samson, PC, Wikswo, JP, Beauchamp, RD, Datta, PK, Freeman, ML Increased cell migration and plasticity in Nrf2-deficient cancer cell lines. Oncogene, 29(25), 3703-14, 2010.
• Segal, BH, Han, W, Bushey, JJ, Joo, M, Bhatti, Z, Feminella, J, Dennis, CG, Vethanayagam, RR, Yull, FE, Capitano, M, Wallace, PK, Minderman, H, Christman, JW, Sporn, MB, Chan, J, Vinh, DC, Holland, SM, Romani, LR, Gaffen, SL, Freeman, ML, Blackwell, TS NADPH oxidase limits innate immune responses in the lungs in mice. PLoS One, 5(3), e9631, 2010.
• Reddy, YT, Sekhar, KR, Sasi, N, Reddy, PN, Freeman, ML, Crooks, PA Novel substituted (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-diones and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones as potent radio-sensitizing agents. Bioorg Med Chem Lett, 20(2), 600-2, 2010.
• Geng, L, Rachakonda, G, Morré, DJ, Morré, DM, Crooks, PA, Sonar, VN, Roti Roti, JL, Rogers, BE, Greco, S, Ye, F, Salleng, KJ, Sasi, S, Freeman, ML, Sekhar, KR Indolyl-quinuclidinols inhibit ENOX activity and endothelial cell morphogenesis while enhancing radiation-mediated control of tumor vasculature. FASEB J, 2009.
• Brown, SL, Sekhar, KR, Rachakonda, G, Sasi, S, Freeman, ML Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Res, 68(2), 364-8, 2008.
• Rachakonda, G, Xiong, Y, Sekhar, KR, Stamer, SL, Liebler, DC, Freeman, ML Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol, 21(3), 705-10, 2008.
• Fukuyo, Y, Inoue, M, Nakajima, T, Higashikubo, R, Horikoshi, NT, Hunt, C, Usheva, A, Freeman, ML, Horikoshi, N Oxidative stress plays a critical role in inactivating mutant BRAF by geldanamycin derivatives. Cancer Res, 68(15), 6324-30, 2008.
• Burk, RF, Hill, KE, Nakayama, A, Mostert, V, Levander, XA, Motley, AK, Johnson, DA, Johnson, JA, Freeman, ML, Austin, LM Selenium deficiency activates mouse liver Nrf2-ARE but vitamin E deficiency does not. Free Radic Biol Med, 44(8), 1617-23, 2008.
• Freeman, ML A commentary on "Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radic Biol Med, 42(8), 1131-2, 2007.
• Al-Ghananeem, AM, Albayati, ZF, Malkawi, A, Sonar, VN, Freeman, ML, Crooks, PA A pharmacokinetic study on Z-(+/-)-2-(1-benzylindole-3-yl-methylene)azabicyclo[2.2.2]octane-3-ol; a novel radio-sensitization agent. Cancer Chemother Pharmacol, 2007.
• Brunoldi, EM, Zanoni, G, Vidari, G, Sasi, S, Freeman, ML, Milne, GL, Morrow, JD Cyclopentenone prostaglandin, 15-deoxy-Delta12,14-PGJ2, is metabolized by HepG2 cells via conjugation with glutathione. Chem Res Toxicol, 20(10), 1528-35, 2007.
• Biswas, S, Guix, M, Rinehart, C, Dugger, TC, Chytil, A, Moses, HL, Freeman, ML, Arteaga, CL Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest, 117(5), 1305-13, 2007.
• Pi, J, Bai, Y, Reece, JM, Williams, J, Liu, D, Freeman, ML, Fahl, WE, Shugar, D, Liu, J, Qu, W, Collins, S, Waalkes, MP Molecular mechanism of human Nrf2 activation and degradation: Role of sequential phosphorylation by protein kinase CK2. Free Radic Biol Med, 42(12), 1797-806, 2007.
• Sekhar, KR, Sonar, VN, Muthusamy, V, Sasi, S, Laszlo, A, Sawani, J, Horikoshi, N, Higashikubo, R, Bristow, RG, Borrelli, MJ, Crooks, PA, Lepock, JR, Roti Roti, JL, Freeman, ML Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway. Cancer Res, 67(2), 695-701, 2007.
• Gao, L, Wang, J, Sekhar, KR, Yin, H, Yared, NF, Schneider, SN, Sasi, S, Dalton, TP, Anderson, ME, Chan, JY, Morrow, JD, Freeman, ML Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3. J Biol Chem, 282(4), 2529-37, 2007.
• Sonar, VN, Thirupathi Reddy, Y, Sekhar, KR, Sasi, S, Freeman, ML, Crooks, PA Novel substituted (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(+/-)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol derivatives as potent thermal sensitizing agents. Bioorg Med Chem Lett, 17(24), 6821-4, 2007.
• Stacy, DR, Ely, K, Massion, PP, Yarbrough, WG, Hallahan, DE, Sekhar, KR, Freeman, ML Increased expression of nuclear factor E2 p45-related factor 2 (NRF2) in head and neck squamous cell carcinomas. Head Neck, 28(9), 813-8, 2006.
• Andrei V. Bakin, Konjeti R. Sekhar, Cammie Rinehart, Xuexian Yan, Michael J. Meredith, Carlos L. Arteaga, and Michael L. Freeman. "Smad3-ATF3 signaling mediates TGF-b suppression of genes encoding Phase II detoxifying proteins.." Free Radical Biology & Medicine., 38375-387, 2005.
• Cao, C, Shinohara, ET, Li, H, Niermann, KJ, Kim, KW, Sekhar, KR, Gleave, M, Freeman, M, Lu, B Clusterin as a therapeutic target for radiation sensitization in a lung cancer model. Int J Radiat Oncol Biol Phys, 63(4), 1228-36, 2005.
• Hong, F, Freeman, ML, Liebler DC "Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane.." Chem Res. Toxicol, 191917-1926, 2005.
• Bakin, AV, Stourman, NV, Sekhar, KR, Rinehart, C, Yan, X, Meredith, MJ, Arteaga, CL, Freeman, ML Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding Phase II detoxifying proteins. Free Radic Biol Med, 38(3), 375-87, 2005.
• Hong, F, Sekhar, KR, Freeman, ML, Liebler, DC Specific patterns of electrophile adduction trigger keap1 ubiquitination and NRF2 activation. J Biol Chem, 2005.
• Lu B, Mu Y, Cao C, Zeng F, Schneider S, Tan J, Price J, Chen J, Freeman M, Hallahan DE. "Survivin as a therapeutic target for radiation sensitization in lung cancer.." Cancer Res., 642840-2845, 2004.
• Ginger L. Milne, Guiseppe Zanoni, Soumya Sasi, Giovanni Vidari, Erik S. Musiek, Michael L. Freeman, and Jason D. Morrow "The Cyclopentenone Product of Lipid Peroxidation, 15-A2t-Isoprostane, is Efficiently Metabolized by HepG2 Cells Via Conjugation with Glutathione. Chem Res. Tox. 17: 17-25, 2004.." Chem Res., 1717-25, 2004.
• Milne, Ginger L, Zanoni, Giuseppe, Porta, Alessio, Sasi, Soumya, Vidari, Giovanni, Musiek, Erik S, Freeman, Michael L, Morrow, Jason D The cyclopentenone product of lipid peroxidation, 15-A2t-isoprostane, is efficiently metabolized by HepG2 cells via conjugation with glutathione. Chem Res Toxicol, 17(1), 17-25, 2004.
• Willis AS, Freeman ML, Summar SR, Williams SM, Dawson E, and Summar ML. "Ethnic specific changes in a critical gene responsible for glutathione synthesis. Free Radical Biology and Medicine. 34: 72-76, 2003.." Free Radical Biology and Medicine, 3472-76, 2003.
• Sekhar KR, Crooks PA, Sonar VN, Friedman DB, Chan JY, Meredith MJ, Starnes JH, Kelton KR, Summar SR, Sasi S, and Freeman ML. "NADPH Oxidase Activity is Essential for Keap1/ Nrf2-Mediated Induction of GCLC in Response to 2-Indol-3-yl-methylenequinuclidin-3-ols.." Cancer Res, 635636-5645, 2003.
• Sekhar KR, Crooks PA, Sonar VN, Friedman DB, Chan JY, Meredith MJ, Starnes JH, Kelton KR, Summar SR, Sasi S, and Freeman ML. "NADPH Oxidase Activity is Essential for Keap1/ Nrf2-Mediated Induction of GCLC in Response to 2-Indol-3-yl-methylenequinuclidin-3-ols.." Cancer Res, 635636-5645, 2003.
• Saha, D., Sekhar, KR, Cao C, Morrow, JD, Choy, H, and Freeman, ML. "The antiangiogenic agent SU5416 downregulates phorbol ester-mediated induction of cyclooxygenase-2 expression by inhibiting NADPH Oxidase activity.." Cancer Res, 636920-6927, 2003.
• Willis, Alecia S, Freeman, Michael L, Summar, Samantha R, Barr, Frederick E, Williams, Scott M, Dawson, Elliott, Summar, Marshall L Ethnic diversity in a critical gene responsible for glutathione synthesis. Free Radic Biol Med, 34(1), 72-6, 2003.
• Willis AS, Freeman ML, Summar SR, Williams SM, Dawson E, and Summar ML. "Ethnic specific changes in a critical gene responsible for glutathione synthesis.." Free Radical Biology and Medicine., 3472-76, 2003.
• Sekhar, Konjeti R, Crooks, Peter A, Sonar, Vijayakumar N, Friedman, David B, Chan, Jeff Y, Meredith, Michael J, Starnes, Joseph H, Kelton, Kathy R, Summar, Samantha R, Sasi, Soumya, Freeman, Michael L NADPH oxidase activity is essential for Keap1/Nrf2-mediated induction of GCLC in response to 2-indol-3-yl-methylenequinuclidin-3-ols. Cancer Res, 63(17), 5636-45, 2003.
• Saha, Debabrata, Sekhar, Konjeti R, Cao, Carolyn, Morrow, Jason D, Choy, Hak, Freeman, Michael L The antiangiogenic agent SU5416 down-regulates phorbol ester-mediated induction of cyclooxygenase 2 expression by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activity. Cancer Res, 63(20), 6920-7, 2003.
• Sekhar KR, Spitz DR, Harris s, Nguyen TT, Meredith MJ, Holt JT, Gius D, Marnett LJ, Summar ML, and Freeman ML. "Redox sensitivie interaction between KIAA0132 and Nrf2 mediates indomethacin –induced expression of g-glutamylcysteine synthetase.." Free Radical Biology and Medicine. , 32650-662, 2002.
• Sekhar KR, Spitz DR, Harris s, Nguyen TT, Meredith MJ, Holt JT, Gius D, Marnett LJ, Summar ML, and Freeman ML. "Redox sensitivie interaction between KIAA0132 and Nrf2 mediates indomethacin –induced expression of g-glutamylcysteine synthetase.." Free Radical Biology and Medicine. , 32650-662, 2002.
• Sekhar, Konjet R, Yan, Xue Xian, Freeman, Michael L Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2. Oncogene, 21(44), 6829-34, 2002.
• Sekhar KR, Yan X, and Freeman ML. "Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to Inrf2.." Oncogene, 216829-6834, 2002.
• Sekhar, Konjeti R, Spitz, Douglas R, Harris, Stephanie, Nguyen, Trung T, Meredith, Michael J, Holt, Jeffrey T, Gius, David, Marnett, Lawrence J, Summar, Marshall L, Freeman, Michael L, Guis, David Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase. Free Radic Biol Med, 32(7), 650-62, 2002.
• Freeman ML, Henle KJ, Dewhirst M W "Hyperthermia." Molecular Biology of Cancer (ed. JR Bertino), 888-900, 2001.
• Brown NJ, Nakamura S, Ma LJ, Nakamura I, Donnert E, Freeman M, Vaughan DE, and Fogo AB "Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo." Kidney Int., 581219-1227, 2000.
• Amorino GP, Freeman ML, Choy H "Enhancement of radiation effects by the estrogen metabolite 2-methoxyestradiol." Radiation Research, 153384-391, 2000.
• Amorino, G P, Freeman, M L, Choy, H Enhancement of radiation effects in vitro by the estrogen metabolite 2-methoxyestradiol. Radiat Res, 153(4), 384-91, 2000.
• Sekhar KR,Soltaninassab SR, Borrelli MJ, Xu ZQ, Meredith MJ, Domann FE, and Freeman ML "Inhibition of the 26S proteasome induces expression of GLCLC, the Catalytic Subunit for -Glutamylcysteine Synthetase." BBRC, 270311-317, 2000.
• Sekhar, K R, Soltaninassab, S R, Borrelli, M J, Xu, Z Q, Meredith, M J, Domann, F E, Freeman, M L Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for gamma-glutamylcysteine synthetase. Biochem Biophys Res Commun, 270(1), 311-7, 2000.
• Soltaninassab SR, Sekhar KR, Meredith ML, and Freeman ML "Multi-faceted regulation of gamma glutamylcysteine synthetase." J. Cell Physiol, 182163-170, 2000.
• Soltaninassab, S R, Sekhar, K R, Meredith, M J, Freeman, M L Multi-faceted regulation of gamma-glutamylcysteine synthetase. J Cell Physiol, 182(2), 163-70, 2000.
• GA Senisterra, HE Frey, ML Freeman, MJ Borrelli, and JR Lepock "Protein destabilization and denaturation: Implications for hyperthermia and the heat shock response." Recent. Res. Devel. Biochem., 265-96, 2000.
• Freeman ML, Borrelli MJ, Meredith MJ, and Lepock JR "On the Path to the Heat Shock Response: Destabilization and Formation of Molten Globule Intermediates, a Consequence of Protein Thiol Modification." Free Radical Biology and Medicine, 26737-745, 1999.
• Sekhar KR and Freeman ML "Autophosphorylation inhibits the activity of gamma- glutamylcysteine synthetase." J. Enzyme Inhibition, 14323-330, 1999.
• Sekhar, K R, Freeman, M L Autophosphorylation inhibits the activity of gamma-glutamylcysteine synthetase. J Enzyme Inhib, 14(4), 323-30, 1999.
• Freeman, M L, Borrelli, M J, Meredith, M J, Lepock, J R On the path to the heat shock response: destabilization and formation of partially folded protein intermediates, a consequence of protein thiol modification. Free Radic Biol Med, 26(5-6), 737-45, 1999.
• Amorino, G P, Freeman, M L, Carbone, D P, Lebwohl, D E, Choy, H Radiopotentiation by the oral platinum agent, JM216: role of repair inhibition. Int J Radiat Oncol Biol Phys, 44(2), 399-405, 1999.
• Amorino G, Freeman ML, Carbone DP, Lebwohl DE, and Choy H "Radioprotection by the oral platinum agent, JM216: Role of repair inhibition." Inter. J. Radiation Oncology, Biology, Physics, 44399-405, 1999.
• Borrelli MJ, Stafford DM, Rausch CM, Freeman ML, Lepock JR, and Corry PM "Diamide induced cytoxicity and thermotolerance in CHO cells." J. Cell. Physiol., 177483-492, 1998.
• Borrelli, MJ, Stafford, DM, Rausch, CM, Bernock, LJ, Freeman, ML, Lepock, JR, Corry, PM Diamide-induced cytotoxicity and thermotolerance in CHO cells. J Cell Physiol, 177(3), 483-92, 1998.
• Abbott DW, Freeman ML, and Holt JT "Double-Strand Break Repair Deficiency and Radiation Sensitivity in BRCA2 Mutant Cancer Cells." JNCI, 90978-985, 1998.
• Abbott, D W, Freeman, M L, Holt, J T Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst, 90(13), 978-85, 1998.
• Brown KE, Kinter MT, Oberley TD, Freeman ML, Frierson HF, Ridnour LA, Tao Y, Oberley LW, and Spitz DR "Enhanced -glutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron overload." Free Radical Biology and Medicine , 24545-555, 1998.
• Meredith MJ, Cusick CL, Soltaninassab S, Sekhar KS, Lu S and Freeman ML "Expression of Bcl-2 increases intracellular glutathione by inhibiting methionine dependent GSH efflux." BBRC, 248458-463, 1998.
• Meredith, MJ, Cusick, CL, Soltaninassab, S, Sekhar, KS, Lu, S, Freeman, ML Expression of Bcl-2 increases intracellular glutathione by inhibiting methionine-dependent GSH efflux. Biochem Biophys Res Commun, 248(3), 458-63, 1998.
• Sekhar, K R, Freeman, M L PEST sequences in proteins involved in cyclic nucleotide signalling pathways. J Recept Signal Transduct Res, 18(2-3), 113-32, 1998.
• Sekhar KR and Freeman ML "PEST sequences in proteins involved in cyclic nucliotide signalling pathways." J. Receptor and Signal Transduction Research, 18113-132, 1998.
• Sekhar KR, Long M, Long, J, Xu ZQ, Summar, ML, and Freeman, ML "Alteration of transcriptional and post-transcriptional expression of -glutamylcysteine synthetase by diethyl maleate." Radiation Res., 147592-597, 1997.
• Sekhar, K R, Long, M, Long, J, Xu, Z Q, Summar, M L, Freeman, M L Alteration of transcriptional and post-transcriptional expression of gamma-glutamylcysteine synthetase by diethyl maleate. Radiat Res, 147(5), 592-7, 1997.
• Freeman, M L, Huntley, S A, Meredith, M J, Senisterra, G A, Lepock, J Destabilization and denaturation of cellular protein by glutathione depletion. Cell Stress Chaperones, 2(3), 191-8, 1997.
• Freeman ML, Huntely SA, Meredith MJ, Senisterra GA, and Lepock JR "Destabilization and denaturation of cellular protein by glutathione depletion." Cell Stress and Chaperones, 2191-198, 1997.
• Senisterra GA, Huntley SA, Escaravage M, Sekhar KR, Freeman ML, Borrelli M, and Lepock JR "Destabilization of the Ca2+-ATPase of Sarcoplasmic reticulum by thiol specific-specific, heat shock inducers results in thermal denaturation at 37 C." Biochemistry , 3611002-11011, 1997.
• Senisterra, GA, Huntley, SA, Escaravage, M, Sekhar, KR, Freeman, ML, Borrelli, M, Lepock, JR Destabilization of the Ca2+-ATPase of sarcoplasmic reticulum by thiol-specific, heat shock inducers results in thermal denaturation at 37 degrees C. Biochemistry, 36(36), 11002-11, 1997.
• Sekhar KR, Meredith MJ, Kerr KD, Soltaninassab SR, Spitz DR, Xu ZQ, and Freeman ML "Expression of glutathione and - glutamylcysteine synthetase mRNA is Jun dependent." BBRC, 234588-593, 1997.
• Sekhar, K R, Meredith, M J, Kerr, L D, Soltaninassab, S R, Spitz, D R, Xu, Z Q, Freeman, M L Expression of glutathione and gamma-glutamylcysteine synthetase mRNA is Jun dependent. Biochem Biophys Res Commun, 234(3), 588-93, 1997.
• McDuffee AT, Senisterra GA, Huntley SA, Lepock JR, Senkhar KR, Morrow JD, and Freeman ML "Proteins containing non-native disulfide bonds generated by oxidative stress may act as signals for the induction of the heat shock response." J. Cellular Physiology , 171143-151, 1997.
• McDuffee, A T, Senisterra, G, Huntley, S, Lepock, J R, Sekhar, K R, Meredith, M J, Borrelli, M J, Morrow, J D, Freeman, M L Proteins containing non-native disulfide bonds generated by oxidative stress can act as signals for the induction of the heat shock response. J Cell Physiol, 171(2), 143-51, 1997.
• Sierra-Rivera, E, Dasouki, M, Summar, M L, Krishnamani, M R, Meredith, M, Rao, P N, Phillips, J A, Freeman, M L Assignment of the human gene (GLCLR) that encodes the regulatory subunit of gamma-glutamylcysteine synthetase to chromosome 1p21. Cytogenet Cell Genet, 72(2-3), 252-4, 1996.
• Sierra-Rivera E, Dasouki M, Summar ML, Krishnamani MRS, Meredith M, Rao PN, Phillips JA, and Freeman ML "Chromosomal localization of the human gene that encodes the regulatory subunit of -glutamylcysteine synthetase to chromosome 1p21." Cytogenetics and Cell Genetics, 72252-254, 1996.
• Freeman ML and Henle KJ. "Hyperthermia." Molecular Biology of Cancer (ed. JR Bertino) Academic Press, 888-900, 1996.
• Jennings, M T, Freeman, M L, Murray, M J Strategies in the treatment of diffuse pontine gliomas: the therapeutic role of hyperfractionated radiotherapy and chemotherapy. J Neurooncol, 28(2-3), 207-22, 1996.
• Sierra-Rivera E, Summar ML, Krishnamani MRS, Phillips III JA, and Freeman ML. "Assignment of the gene that codes the heavy subunit of gamma-glutamylcysteine synthetase to human chromosome 6.." Cytogenetics and Cell Genetics , 70278-279, 1995.
• Sierra-Rivera, E, Summar, M L, Dasouki, M, Krishnamani, M R, Phillips, J A, Freeman, M L Assignment of the gene (GLCLC) that encodes the heavy subunit of gamma-glutamylcysteine synthetase to human chromosome 6. Cytogenet Cell Genet, 70(3-4), 278-9, 1995.
• Sierra-Rivera E, Summar ML, Krishnamani MRS, Phillips III JA, and Freeman ML "Assignment of the gene that codes the heavy subunit of -glutamylcysteine synthetase to human chromosome 6." Cytogenetics and Cell Genetics , 70278-279, 1995.
• Freeman, M L, Borrelli, M J, Syed, K, Senisterra, G, Stafford, D M, Lepock, J R Characterization of a signal generated by oxidation of protein thiols that activates the heat shock transcription factor. J Cell Physiol, 164(2), 356-66, 1995.
• Sierra-Rivera, E, Meredith, M J, Summar, M L, Smith, M D, Voorhees, G J, Stoffel, C M, Freeman, M L Genes regulating glutathione concentrations in X-ray-transformed rat embryo fibroblasts: changes in gamma-glutamylcysteine synthetase and gamma-glutamyltranspeptidase expression. Carcinogenesis, 15(7), 1301-7, 1994.
• Sierra-Rivera, E, Meredith, M J, Voorhees, G J, Oberley, L W, Eisert, D R, Freeman, M L Synthesis of heat shock proteins following oxidative challenge: role of glutathione. Int J Hyperthermia, 10(4), 573-86, 1994.
• Sierra-Rivera, E, Voorhees, G J, Freeman, M L Gamma irradiation increases hsp-70 in Chinese hamster ovary cells. Radiat Res, 135(1), 40-5, 1993.
• Freeman, M L, Sierra-Rivera, E, Voorhees, G J, Eisert, D R, Meredith, M J Synthesis of hsp-70 is enhanced in glutathione-depleted Hep G2 cells. Radiat Res, 135(3), 387-93, 1993.
• Oikawa T, Freeman ML, Lo W, Vaughan DE, and Fogo A. "Modulation of plasminogen activator inhibitor-1(PAI-1) in vivo: A new mechanism for the anti-fibrotic effect of rennin-angiotensin inhibition.." Kidney Inter, 51164-172, 1992.
• Saunders, E L, Meredith, M J, Eisert, D R, Freeman, M L Depletion of glutathione after gamma irradiation modifies survival. Radiat Res, 125(3), 267-76, 1991.
• Saunders, E L, Maines, M D, Meredith, M J, Freeman, M L Enhancement of heme oxygenase-1 synthesis by glutathione depletion in Chinese hamster ovary cells. Arch Biochem Biophys, 288(2), 368-73, 1991.
• Atsmon, J, Freeman, M L, Meredith, M J, Sweetman, B J, Roberts, L J Modulation of the antiproliferative activity of 9-deoxy-delta 9,delta 12(E)-PGD2 by conjugation with intracellular glutathione. Adv Prostaglandin Thromboxane Leukot Res, 21B887-90, 1991.
• Atsmon, J, Freeman, M L, Meredith, M J, Sweetman, B J, Roberts, L J Conjugation of 9-deoxy-delta 9,delta 12(E)-prostaglandin D2 with intracellular glutathione and enhancement of its antiproliferative activity by glutathione depletion. Cancer Res, 50(6), 1879-85, 1990.
• Freeman, M L, Spitz, D R, Meredith, M J Does heat shock enhance oxidative stress? Studies with ferrous and ferric iron. Radiat Res, 124(3), 288-93, 1990.
• Freeman, M L, Meredith, M J, Eisert, D R Failure of chronic glutathione elevation to reduce cytotoxicity produced by exposure to cis-diamminedichloroplatinum(II), ionizing radiation, or hyperthermia. Cancer Res, 50(17), 5296-300, 1990.
• Freeman, M L, Meredith, M J Glutathione conjugation and induction of a 32,000 dalton stress protein. Biochem Pharmacol, 38(2), 299-304, 1989.
• Freeman, M L, Meredith, M J Measurement of protein thiols after heat shock using 3-(-N-maleimido-propionyl) biocytin labeled proteins separated by SDS-PAGE and electroluted onto nitrocellulose: thiol blotting. Radiat Res, 117(2), 326-33, 1989.
• Freeman, M L, Meredith, M J Modulation of diamide toxicity in thermotolerant cells by inhibition of protein synthesis. Cancer Res, 49(16), 4493-8, 1989.
• Freeman, M L, Meredith, M J, Laszlo, A Depletion of glutathione, heat shock protein synthesis, and the development of thermotolerance in Chinese hamster ovary cells. Cancer Res, 48(24 Pt 1), 7033-7, 1988.
• Freeman, M L, Meredith, M J Subcellular localization of glutathione and thermal sensitivity. Radiat Res, 115(3), 461-71, 1988.
• Freeman, ML, Scidmore, NC, Malcolm, AW, Meredith, MJ Diamide exposure, thermal resistance, and synthesis of stress (heat shock) proteins. Biochem Pharmacol, 36(1), 21-9, 1987.
• Freeman, M L, Scidmore, N C, Meredith, M J Inhibition of heat shock protein synthesis and thermotolerance by cycloheximide. Radiat Res, 112(3), 564-74, 1987.
• Freeman, ML, Meredith, MJ The effect of GSH depletion on thermal radiosensitization. Int J Radiat Oncol Biol Phys, 13(9), 1371-5, 1987.
• Freeman, ML, Malcolm, A Acid modification of thermal damage and its relationship to nutrient availability. Int J Radiat Oncol Biol Phys, 11(10), 1823-6, 1985.
• Freeman, ML, Malcolm, AW, Meredith, MJ Decreased intracellular glutathione concentration and increased hyperthermic cytotoxicity in an acid environment. Cancer Res, 45(2), 504-8, 1985.
• Freeman, M L, Malcolm, A W, Meredith, M J Glutathione pool size affects cell survival after hyperthermic treatment. Cell Biol Toxicol, 1(3), 213-21, 1985.
• Freeman, ML, Malcolm, AW, Meredith, MJ Role of glutathione in cell survival after hyperthermic treatment of Chinese hamster ovary cells. Cancer Res, 45(12 Pt 1), 6308-13, 1985.
• Freeman, ML, Sierra, E An acidic extracellular environment reduces the fixation of radiation damage. Radiat Res, 97(1), 154-61, 1984.
• Freeman, ML, Sierra, E, Hall, EJ The repair of sublethal damage in diploid human fibroblasts: a comparison between human and rodent cell lines. Radiat Res, 95(2), 382-91, 1983.
• Goldhagen, PE, Freeman, ML, Hall, EJ Studies with encapsulated 125I sources. I. Apparatus and dosimetry for determination of relative biological effectiveness. Int J Radiat Oncol Biol Phys, 8(8), 1347-53, 1982.
• Freeman, ML, Goldhagen, P, Sierra, E, Hall, EJ Studies with encapsulated 125I sources. II. Determination of the relative biological effectiveness using cultured mammalian cells. Int J Radiat Oncol Biol Phys, 8(8), 1355-61, 1982.
• Freeman, ML, Sierra, E, Deitch, AD, Cubbon, RM The repair of potentially lethal and sublethal damage in unfed plateau-phase cultures irradiated at 0.78 Gy/hr. Radiat Res, 92(3), 596-603, 1982.
• Freeman, ML, Holahan, EV, Highfield, DP, Raaphorst, GP, Spiro, IJ, Dewey, WC The effect of pH on hyperthermic and x ray induced cell killing. Int J Radiat Oncol Biol Phys, 7(2), 211-6, 1981.
• Freeman, ML, Boone, ML, Ensley, BA, Gillette, EL The influence of environmental pH on the interaction and repair of heat and radiation damage. Int J Radiat Oncol Biol Phys, 7(6), 761-4, 1981.
• Dewey, WC, Freeman, ML Rationale for use of hyperthermia in cancer therapy. Ann N Y Acad Sci, 335372-8, 1980.
• Freeman, ML, Raaphorst, GP, Hopwood, LE, Dewey, WC The effect of pH on cell lethality induced by hyperthermic treatment. Cancer, 45(9), 2291-2300, 1980.
• Raaphorst, GP, Sapareto, SA, Freeman, ML, Dewey, WC Changes in cellular heat and/or radiation sensitivity observed at various times after trypsinization and plating. Int J Radiat Biol Relat Stud Phys Chem Med, 35(2), 193-7, 1979.
• Raaphorst, GP, Freeman, ML, Dewey, WC Radiosensitivity and recovery from radiation damage in cultured CHO cells exposed to hyperthermia at 42.5 or 45.5 degrees C. Radiat Res, 79(2), 390-402, 1979.
• Freeman, ML, Raaphorst, GP, Dewey, WC The relationship of heat killing and thermal radiosensitization to the duration of heating at 42 degrees C. Radiat Res, 78(1), 172-5, 1979.
• Freeman, ML, Dewey, WC, Hopwood, LE Effect of pH on hyperthermic cell survival. J Natl Cancer Inst, 58(6), 1837-9, 1977.