September 1st, 2009 by djwweb

David J. Waxman

Professor of Cell and Molecular Biology, Department of Biology
Professor of Medicine, Boston University School of Medicine

Ph.D., Harvard University, 1980

Areas of interest:  Molecular endocrinology and cell signaling through transcriptional networks; Cancer gene therapy and pharmacology; Liver genes and transcriptional control; Orphan receptors and responses to environmental chemicals

Website: { link to personal website}
Phone: (617) 353-7402

A major goal of our laboratory is to elucidate hormone regulatory circuits that govern sex-specific gene expression in the liver.  A second goal is to apply our knowledge on cytochrome P450 enzyme systems, which metabolize structurally diverse steroids, drugs and environmental chemicals, to improve human health.  These efforts are exemplified by P450-based gene therapies that we have developed to improve the responsiveness of tumors to cancer chemotherapeutic drugs.

1) Endocrine control of hepatic gene expression. Our studies are designed to elucidate the transcriptional networks that govern the developmental and sex-dependent regulation that characterizes more than1000 genes in mammalian liver.  Current research projects use genome-wide expression and tiling microarrays (ChIP-chip) combined with classical molecular and bioinformatic tools to investigate: (a) gene regulatory circuits through which the ultraradian pattern of pituitary growth hormone (GH) secretion either masculinizes hepatic gene expression (pulsatile GH secretion) or feminizes gene expression (near-continuous GH secretion); (b) the role of the plasma membrane GH receptor in GH signaling and its activation of STAT5b, a tyrosine-phosphorylated transcription factor that is required for ~90% of sex-specific gene expression in the liver; and (c) epigenetic regulatory mechanisms that impact these processes.

2) Cytochrome P450 metabolism of anti-cancer drugs and foreign chemicals. Our current research emphasizes: (a) development of P450 gene-based cancer gene therapies to sensitize tumor cells to cancer chemotherapeutic prodrugs; (b) elucidation of the actions of tumor endothelial cell-directed anti-angiogenic drugs and their impact on classic cancer chemotherapies; and (c) toxicological consequences of the modulation of P450 gene expression in response to foreign chemical exposure.

BI556:  Membrane Biochemistry

Ma J, Waxman DJ.  Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib.  (2008) Molec Cancer Ther 7: 79-89.

Clodfelter KH, Miles GD, Wauthier V, Holloway MG, Zhang X, Hodor P, Ray WJ, Waxman DJ.  Role of STAT5a in regulation of sex-specific gene expression in female but not male mouse liver revealed by microarray analysis.  (2007) Physiol Genomics 31: 63-74.

Ma J, Waxman DJ.  Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment.  (2007) Molec Cancer Ther 6: 2879-90.

Holloway MG, Cui Y, Laz EV, Hosui A, Hennighausen L, Waxman DJ.  Loss of sexually dimorphic liver gene expression upon hepatocyte-specific deletion of Stat5a-Stat5b locus.  (2007) Endocrinology 148: 1977-1986.

Chen CS, Jounaidi Y, Su T, Waxman DJ.  Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model.  (2007) Cancer Gene Ther 14: 935-44.

Laz EV, Holloway MG, Chen CS, Waxman DJ.  Characterization of three growth hormone-responsive transcription factors preferentially expressed in adult female liver.  (2007) Endocrinology 148: 3327-3337.

Clodfelter KH, Waxman DJ, Vajda S.  Computational solvent mapping reveals the importance of local conformational changes for broad substrate specificity in mammalian cytochromes P450.  (2006) Biochemistry 45: 9393-9407.

Clodfelter KH, Holloway MG, Hodor P, Park SH, Ray WJ, Waxman DJ.  Sex-dependent liver gene expression is extensive and largely dependent upon signal transducer and activator of transcription 5b (STAT5b): STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis.  (2006) Molec Endocrinol 20: 1333-1351.