Orla Conneely, Ph.D.
Department of Molecular and Cellular Biology
Baylor College of Medicine
Ph.D., National University of Ireland, Republic of Ireland
Postdoc, Baylor College of Medicine
The objective of our research is to establish the role of nuclear receptors in vertebrate development and carcinogenesis. Nuclear receptors comprise a large family of structurally related transcription factors regulating the expression of genes that control a variety of developmental and physiological responses to diverse stimuli. Specifically, we aim to elucidate the physiological role of members of two different subfamilies of nuclear receptors, progesterone receptors and the NR4A subfamily of nuclear receptors.
Progesterone is a key regulator of female reproductive activity. The effects of progesterone are mediated by two receptor proteins (PR), termed A and B, that arise from a single gene and act as ligand activated transcription factors to regulate the expression of specific sets of target genes in progesterone responsive tissues. The overall objective of this research project is to establish the selective physiological roles of the individual PR isoforms in the female reproductive tract and during mammary gland development and tumorigenesis.
To this end, we have used gene targeting in embryonic stem cells to selectively ablate expression of either the PR-A (PRAKO) or PR-B (PRBKO) isoform in mice. Using these models we have shown that PR-A and PR-B mediate mostly distinct but partially overlapping reproductive tissue selective physiological responses to progesterone. Our goals are 1) to understand the molecular genetic signaling pathways that are regulated by each of these isoforms through identification of PR dependent target genes in responsive tissues and 2) to expose the contribution of deregulated progesterone receptor signaling to tumorigenesis.
Nor-1 and nur77 are members of the NR4A subfamily of nuclear receptor transcription factors. NR4A receptors have highly homologous amino acid sequences and can interact with common cis-acting DNA elements to regulate overlapping target genes. Unlike most nuclear receptors, NR4A subfamily members are not ligand activated and can function as constitutively active transcription factors. In addition, they are products of immediate early genes whose expression is regulated in a cell specific manner in response to a variety of extracellular mitogenic, apoptotic and differentiative stimuli and whose activity can be regulated in a positive or negative manner by specific phosphorylation cascades.
To uncover the essential physiological roles of NR4A receptors, we have generated null mutant mice in which the expression of these proteins has been disrupted. Our current research objectives are based on our recent discovery that mice deficient in both nur77 and nor-1 develop rapidly lethal and transplantable acute myeloid leukemia (AML). Our findings indicate that nor1 and nur77 function as tumor suppressor genes that restrict proliferative expansion of hematopoietic stem or myeloid progenitor cells by regulation of apoptosis and/or cell cycle exit. They also suggest that inactivation of nur77 and nor1 by oncogenic signaling pathways may
play a key role in the development of human AML disease. Our research goals are t
- Identify leukemic stem cell populations that give rise to AML in nor1/nur77 null mutant mice and examine the molecular mechanisms responsible for unrestrained
expansion of the myeloid compartment in the absence these nuclear receptors,
- Determine whether inactivation of nor1 and nur77 by AML oncogenes plays a role in
proliferation and survival of human AML cells and
- Determine whether nor1 and nur77 serve as novel molecular targets for therapeutic intervention in human AML.
Ponnio T, Conneely OM. (2004) nor-1 regulates hippocampal axon guidance, pyramidal cell survival, and seizure susceptibility. Mol Cell Biol. 24:9070-8.
Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM. (2003) Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A. 100:9744-9.
Ward PP, Mendoza-Meneses M, Cunningham GA, Conneely OM. (2003) Iron status in mice carrying a targeted disruption of lactoferrin. Mol Cell Biol. 23:178-85.
Conneely OM, Mulac-Jericevic B, DeMayo F, Lydon JP, O'Malley BW. (2002) Reproductive functions of progesterone receptors. Recent Prog Horm Res. 57:339-55. Review.
Ponnio T, Burton Q, Pereira FA, Wu DK, Conneely OM. (2002) The nuclear receptor Nor-1 is essential for proliferation of the semicircular canals of the mouse inner ear. Mol Cell Biol. 22:935-45.
Conneely OM (2001) Female steroid hormone action. Endocrinology 142:2194.
Mulac-Jericevic B, Mullinax R, De Mayo F, Lydon JP and Conneely OM. 2000. Tissue selective mediation of the reproductive functions of progesterone by the progesterone receptor B isoform. Science. 289:1641-1828.
Tibbetts T, DeMayo F, Rich S, Conneely OM, O'Malley BW. 1999. Progesterone Receptors in the thymus are required for thymic involution during pregnancy and for normal fertility. Proc. Natl. Acad. Sci. 96:12021-12026.