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We are broadly interested in signaling events and transcriptional programs that regulate endocrine and neuroendocrine tissue development. Our research focuses on NR5A nuclear hormone receptors because of their critical roles in endocrine organogenesis, steroid and cholesterol homeostasis and metabolism. After showing that phospholipids serve as NR5A ligands we found that similar to plasma membrane signaling by PIP2 and PIP3, nuclear PI3-kinases and -phosphatases are able to act on the exposed-bound phospholipid headgroup and modulate receptor activity. This mechanism illustrates how nuclear lipid signaling can be used to regulate gene expression.
NR5A receptors are excellent substrates for sumoylation, and as such are ideal for understanding how this PTM regulates gene expression and cellular proliferation. Our recent study established that SUMO-less SF-1 mice exhibit inappropriate activation of SUMO-sensitive genes involved in cell specification and proliferation. Using a gene-expression HTS, we are exploiting this transcriptional readout to identify genetic pathways and drugs that promote or diminish NR5A sumoylation. This screen may yield useful leads for targeting metabolic diseases and cancers.
One of our current biological interest lies in the development of a neuroendocrine center, the ventromedial hypothalamus (VMH), which controls metabolic homeostasis and reproduction. Using mouse genetics we recently mapped the embryonic and neonatal efferent projections from this region (left), and created a mouse model of gender specific obesity.
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Cheung, C., Kurrasch, D.M., Liang, J. and H.A. Ingraham, Genetic Labeling Of SF-1 Neurons Reveals VMH Circuitry Beginning At Neurogenesis And The Emergence Of A Separate Non-SF-1 Neuronal Cluster In The Ventrolateral VMH, Epub, Journal of Comparative Neurology (2012).
Blind, R.D., Suzawa, M. and H.A. Ingraham, Direct modification and regulation of the nuclear protein-lipid complex NR5A1-PIP2 by the PI3-kinase IPMK. (Cover and Podcast) Science Signaling 2012 Jun 19;5(229) PMID: 22715467 (2012).
Lee, F.Y., Faivre, E.J., Suzawa, M., Lontok, E., Ebert, D., Cai, F., Belsham, D.D. and H.A. Ingraham,, Eliminating SF-1 (NR5A1) Sumoylation In Vivo Results in Ectopic Hedgehog Signaling and Disruption of Endocrine Development. (Cover, Preview, and Podcast), Developmental Cell 21:315-327 (2011). PMCID: PMC3157481
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Holly Ingraham, Ph.D.
Professor and Associate Vice Chair of Cellular and Molecular Pharmacology
Herzstein Distinguished Investigator
1550 4th Street, Rock Hall 284E, San Francisco, CA 94143
holly.ingraham@ucsf.edu
Lab Phone: 415-476-3401 — Office Phone: 415-476-2731 |
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