David M. Kaetzel, Ph.D.
Professor and Vice-chair
University of Maryland, 1981.
Office: MS-301 Chandler Medical Center (0298)
Lab: MS-363; (859) 257-1290
Lab office: (859) 323-8703
Tel: (859) 257-6558
Our laboratory is focused on the elucidation of molecular mechanisms underlying the progression of cancer cells to metastatic forms, the primary cause of death in human malignancies. Our NCI-funded research program deals with NM23, the first metastasis suppressor gene to be discovered. We have demonstrated that the NM23-H1 isoform possesses 3'-5' exonuclease activity in vitro, strongly suggesting a role in DNA repair and antimutator activity in human cancer. Current efforts are being directed to validation of this hypothesis in melanoma and breast cancer, using both cell culture and mouse models. A significant component of this research has involved the characterization of DNA repair complexes with which the NM23-H1 molecule interacts, with the prediction such processes will lead to new insights into how cancer cells progress genetically to the metastatic phenotype. In addition, our laboratory has maintained a long-standing interest in transcriptional mechanisms that drive overexpression of platelet-derived growth factor (PDGF) in cancer and metastasis. We have recently shown that the PDGF-A gene contains an enhanceosome structure located in the far upstream (5'-distal) region that appears to play an important role in cancer cell-specific transcription. The element also mediates responsiveness of the PDGF-A gene to such nuclear receptor ligands as 1,25-dihydroxyvitamin D and retinoic acid. We are using our progress in these areas to develop new strategies to block progression to metastasis and to target metastatic cells for destruction, or at the very least, reduce their virulence in human cancer.
Recent Publications
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Pedigo, N., Zhang, H., Mishra, A., McCorkle, R., Ormerod, A.K. and Kaetzel, D.M. (2007)
Retinoic acid inducibility of the PDGF-A gene is mediated by a novel response element in the 5'-distal region. Gene Expr., in press.
Kaetzel, D.M., Zhang, Q., Yang, M., McCorkle, J.R., Craven, R. (2006)
Potential roles of 3'-5' exonuclease activity of NM23-H1 in DNA repair and malignant progression. J. Bioenerg. Biomembr. 38: 163-167
Ma, D., Nutt, C.L., Shanehsaz, P., Peng, X., Louis, D. and Kaetzel, D.M. (2005)
Autocrine PDGF-dependent gene expression in glioblastoma cells is mediated largely by activation of the transcription factor SRE-BP, and is associated with altered genotype and patient survival in human brain tumors. Cancer Research 65: 5523-5534.
Ma, D., McCorkle, R. and Kaetzel, D.M. (2004)
The metastasis suppressor NM23-H1 possesses 3'-to-5' exonuclease activity. J. Biol. Chem. 279:18073-18084.
Pedigo, N., Zhang, X.-H., Bruno, E.C., Kaetzel, C.S., Dugan, A., Koszewski, N. and Kaetzel, D.M. (2005)
A 5'-distal enhanceosome in the PDGF-A gene is activated in choriocarcinoma cells via ligand-independent binding of vitamin D receptor and constitutive jun kinase signaling. Oncogene 24:2654-2666.
Zhang, Q., Pedigo, N.G., Shenoy, S., Khalili, K. and Kaetzel, D.M. (2005)
Purα activates PDGF-A gene transcription via interactions with a G-rich, single-stranded region of the promoter. Gene 348C: 25-32.
Pedigo N, Zhang H, Koszewski NJ, Kaetzel DM. (2003)
A 5'-distal element mediates vitamin D-inducibility of PDGF-A gene transcription.
Growth Factors. 21:151-60.
Kaetzel DM. (2003)
Transcription of the platelet-derived growth factor A-chain gene.
Cytokine Growth Factor Rev. 14:427-46.
Ma D, Xing Z, Liu B, Pedigo NG, Zimmer SG, Bai Z, Postel EH, Kaetzel DM. (2002)
NM23-H1 and NM23-H2 repress transcriptional activities of nuclease-hypersensitive elements in the platelet-derived growth factor-A promoter.
J Biol Chem 277:1560-7.
Postel E, Rooney J, Berberich S and Kaetzel DM. (2000)
Human NM23/nucleoside diphosphate entry into studies of the linkage between vitamin D. kinase regulates gene expression through DNA binding
to nuclease-hypersensitive transcriptional elements (Invited Review).
J Bioenergetics and Biomembranes 32: 277-284.
Schilling DS, Hujer A, Morgan D, DeMoll E, Bummer P, Fenstermaker RA and Kaetzel DM. (1998)
The loop III region of platelet-derived growth factor (PDGF) B-chain mediates binding to PDGF receptors and heparin.
Biochem J 333:637-644.
Maul RS, Reid JD, Zhang H and Kaetzel DM. (1998)
Identification of a cell-specific enhancer in the distal 5'-region of the platelet-derived growth factor A-chain gene.
J Biol Chem 273:33239-33246.
Liu B, Maul RS and Kaetzel DM Jr. (1996)
Repression of PDGF A-chain gene transcription by multiple silencer elements.
J Biol Chem 271:26281-26290.
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