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Transcriptional Control of Development and Cancer
Transcription factors are responsible for coordinating gene expression during cell growth and differentiation. Consequently, the inappropriate expression of these molecules can lead to metabolic diseases, developmental defects, and cancer. Our goal is to learn about these processes in the context of the AP-2 family of transcription factors: AP-2α, AP-2β, and AP-2γ. These genes are key regulators of mouse embryogenesis and have been linked to human birth defects and breast cancer. We employ both in vitro and in vivo analyses, particularly mouse molecular genetics, to study the regulation and function of the AP-2 proteins in mammalian development and cancer. We have shown that mice lacking the AP-2α gene die at birth and have major defects affecting the head and trunk. The AP-2α gene is required for at least six independent developmental processes - formation of the neural tube, face, eye, body wall, limbs, and cardiovascular system. Recently we have succeeded in knocking out a second member of the AP-2 gene family - AP-2γ. We have found that AP-2γ knockout mice die prior to gastrulation, soon after implantation in the uterus. Delving deeper, we have discovered that AP-2γ is needed solely in the extraembryonic tissues that give rise to the placenta and may control stem cell populations that are important for establishing maternal-fetal interactions. Since the AP-2 genes control multiple aspects of mammalian development, we have now generated mice containing conditional alleles of both the AP-2α and AP-2γ genes. These mice will be employed to address how the AP-2 genes regulate specific developmental processes, such as neural crest cell function, placental formation, and craniofacial patterning.
With respect to human disease, over-expression of the AP-2α and AP-2γ transcription factors occurs in many breast cancer biopsies. This is an important observation since the AP-2 proteins can alter the expression of several genes linked with the progression of breast cancer, including ERBB2 and the estrogen receptor. We have now mimicked the human situation by generating transgenic animals that over-express AP-2α in the mouse mammary gland. Analysis of these transgenic animals indicates that the AP-2 proteins can act like tumor suppressors to inhibit cell proliferation. We are now generating mammary gland-specific knockouts of the AP-2 genes to gain further insight into their role into normal breast development and breast cancer. Selected Publications
Feng, W., J. Huang, J. Zhang and T. Williams. (2008) Identification and analysis of a conserved Tcfap2a intronic enhancer element required for expression in facial and limb bud mesenchyme. Mol. Cell. Biol. 28, 315-325. Wang, X., A. Pasolli, T. Williams, and E. Fuchs. (2008) AP-2 factors act in concert with Notch to transcriptionally orchestrate terminal differentiation in skin epidermis. J. Cell. Biol. 183, 37-48. Winger, Q., J. Huang, H. Auman, M. Lewandoski, and T. Williams. (2006) Analysis of Transcription Factor AP-2 Expression and Function during Mouse Pre-implantation Development. Biology of Reproduction 75, 324–333. Brewer S, and T Williams (2004) Finally, a sense of closure? Animal models of human ventral body wall defects (Review) Bioessays 26, 1307-21. Brewer S, W Feng, J Huang, S Sullivan and T Williams (2004) Wnt1-Cre mediated deletion of AP2alpha causes multiple neural crest related defects. Dev. Biol. 267, 135-52. Nelson D and T Williams (2004) Frontonasal process-specific disruption of AP-2a results in postnatal midfacial hypoplasia, vascular anomalies, and nasal cavity defects. Dev. Biol. 267, 72-92. Zhang J, Brewer S, Huang J, Williams T (2003) Overexpression of transcription factor AP-2alpha suppresses mammary gland growth and morphogenesis. Dev Biol. Apr;256(1):127-45. Auman HJ, Nottoli T, Lakiza O, Winger Q, Donaldson S, Williams T (2002) Transcription factor AP-2gamma is essential in the extra-embryonic lineages for early postimplantation development. Development. Jun;129(11):2733-47. Turner BC, et al (1998) Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways. Cancer Research 58, 5466-5472. Nottoli T, S Hagopian-Donaldson, J Zhang, A Perkins and T Williams (1998) AP-2-null cells disrupt morphogenesis of the eye, face and limbs in chimeric mice. Proc. Natl. Acad. Sci. USA 95, 13714-13719. Zhang, J., S. Hagopian-Donaldson, G. Serbedzija, J. Elsemore, D. Plehn-Dujowich, A.P. McMahon, R.A. Flavell and T. Williams (1996). Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. Nature 381, 238-241. |
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