Research Interests

Selected Publications

E-mail:
butler@mdanderson.org

Andrew P. Butler, Ph. D.

Research interests

Transcriptional regulation, signal transduction, cell cycle, protein phosphorylation

Current Research

My laboratory is interested in transcriptional regulation of genes involved in cell proliferation and cell cycle control, whose deregulation contributes to the development of cancer.

In one current project, we are collaborating with Dr. Rodney Nairn to investigate transcriptional regulation of cell-cycle related genes in Xiphophorus fish. Interspecies hybrids of Xiphophorus represent a genetic model for melanoma susceptibility. In this model, a p16 homologue (CDKN2AB) has been identified as a candidate tumor suppressor gene. Because p16 has been implicated in the development of human melanoma, this is an excellent model in which to investigate the role of p16 in cancer. We are characterizing the transcriptional regulation of CDKN2AB, as well as it's interactions with other proteins involved in G1 checkpoint control. Our analysis of the CDKN2AB promoter demonstrates that CDKN2AB transcription is aberrantly regulated in melanoma cells, and we have identified a region of the promoter that confers high levels of expression in melanoma. We are presently identifying Xiphophorus transcription factors which regulate CDKN2AB. In this regard, we have cloned a Xiphophorus forkhead transcription factor, FoxO5, and have begun to characterize its role in regulation of cell proliferation and apoptosis. FoxO transcription factors are regulated by signal transduction pathways activating the Akt protein kinase, and we are investigating the effects of aberrant signaling in melanoma on the ability of FoxO5 to regulate cell proliferation. To accomplish this, we are using siRNA approaches to inactivate Akt signaling, and we are also characterizing the effects on cell growth of FoxO5 mutants which are either constitutively active or dominant negative transcription factors. These studies have also led us to investigate the role of FoxO gene products in cell survival and cancer development in mammalian models.

A second project is the analysis of signal transduction pathways and transcription regulation of the rat ornithine decarboxylase (ODC) gene. ODC is expressed at high levels in human cancer, is rapidly induced by tumor promoters, and contributes towards oncogenic transformation. We have used reporter gene assays, site-directed mutagenesis and DNA-protein binding studies to identify factors involved in regulation of ODC, particularly those required for ODC induction by phorbol ester tumor promoters. Using a cell system deficient in transcription factor Sp1, we demonstrated that Sp1 is essential for ODC transcription, and that the related transcription factor Sp3 inhibits the action of Sp1. Furthermore, we showed that transcriptional activity of Sp1 is regulated by serum growth factors and is increased in epidermal tumors. Current studies are aimed at understanding the role of transcriptional co-activators in regulating induction of ODC by tumor promoters.

Selected References

1. Liu, J-W, Chandra, D, Rudd, MD, Butler, AP, Pallotta, V, Brown, D, Coffer, PJ, Tang, DG (2005) "Induction of pro-survival molecules by apoptotic stimuli: Involvement of FOXO3a and ROS and implications for cancer therapy," Oncogene 24:2020-2031.
2. Rudd, M.D., D. A. Johnston, S. Kazianis and A. P. Butler (2003) "Cloning and analysis of a FoxO transcription factor from Xiphophorus," Gene 302: 31-41.
3. Zhao, B. and A. P. Butler (2001) "Core promoter involvement in the induction of rat ornithine decarboxylase by phorbol esters," Molec. Carcinogenesis 32:92-99
4. Nairn, R.S., Kazianis, S. Della Coletta, L. Trono, D., Butler, A.P., Walter, R.B. and Morizot, D.C. (2001) "Genetic analysis of susceptibility to spontaneous and UV carcinogenesis in Xiphophorus hybrid fish" Marine Biotech. 3, S24-S36.
5. Kumar, A. P. and A. P. Butler (1997) "Transcription factor Sp3 antagonizes activation of the ornithine decarboxylase promoter by Sp1" Nucleic Acids Res. 25, 2012-2019.
6. Kumar, A. P., P. K. Mar, B. Zhao, R. L. Montgomery, D.-C. Kang, and A. P. Butler, (1995). Regulation of rat ornithine decarboxylase promoter activity by binding of transcription factor Sp1. J. Biol. Chem. 270, 4341-4348.