Faculty

Jorge Iniguez-Lluhi

Associate Professor of Pharmacology

Ph.D. University of Texas Southwestern Medical Center
Dallas, TX.
Postdoctoral Fellow, University of California San Francisco

Research Focus: Protein regulation by Ubiquitin-like post-translational modifications; Mechanism of action and pathobiology of steroid hormone receptors; Basic mechanisms of transcriptional regulation; Drug discovery and development.

Phone: 734.615.6565
E-mail: iniguez@umich.edu

 

The ability to rapidly regulate protein activity is a key element of normal physiology and the target of most drugs.  We are interested in reversible covalent and non-covalent mechanisms of protein regulation.

The first involves the covalent post-translational modification of proteins through the conjugation of Ubiquitin-like molecules. We focus on sequence-specific transcription factors and ion channels and how conjugation of Small Ubiquitin-like MOdifier proteins (SUMOylation) regulates the activity and localization of this eclectic group of proteins.  We have demonstrated that SUMOylation is a powerful inhibitory mechanism for transcription factors that acts in a promoter context dependent manner by using a unique protein-protein interaction surface.  Remarkably, SUMOylation also targets membrane proteins such as voltage gated ion channels and regulates their function by altering their intrinsic biophysical properties and trafficking to and from the plasma membrane. We are currently examining how alterations in SUMOylation are responsible for multiple human diseases and are developing small molecules to manipulate this pathway for therapeutic applications in prostate cancer and cardiac arrhythmias.

The second mechanism of protein control involves the non-covalent binding of small ligands by members of the nuclear receptor superfamily, including the glucocorticoid and androgen receptors. Through the design of novel ligands, we are extending the intrinsic regulatory repertoire of these receptors.  By exploiting small molecule noncovalent interactions with transcriptional coregulators, we are exploring how to control the transcriptional response of these receptors in a directed way to achieve selective gene regulatory patterns that are effective therapeutically while avoiding the numerous deleterious side effects of conventional ligands.

 

Representative Publications

  1. Danciu TE, Chupreta S, Cruz O, Fox JE, Whitman M, Iñiguez-Lluhí JA. Small Ubiquitin-like Modifier (SUMO) Modification Mediates Function of the Inhibitory Domains of Developmental Regulators FOXC1 and FOXC2. J Biol Chem. 2012;287(22):18318-29.

  2. Snider NT, Weerasinghe SVW, Iñiguez-Lluhí JA, Herrmann H, Omary MB. Keratin hypersumoylation alters filament dynamics and is a marker for human liver disease and keratin mutation. J Biol Chem. 2011;286(3).

  3. Mukherjee S, Thomas M, Dadgar N, Lieberman AP, Iniguez-Lluhi JA. Small ubiquitin-like modifier (SUMO) modification of the androgen receptor attenuates polyglutamine-mediated aggregation. J Biol Chem. 2009;284(32):21296-306. PMCID: PMCID 2755854.

  4. Figueroa-Romero C, Iñiguez-Lluhí JA, Stadler J, Chang CR, Arnoult D, Keller PJ, et al. SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. Faseb J. 2009.

  5. Holmstrom  SE, Chupreta S, So AY, Iñiguez Lluhí JA. SUMO-Mediated Inhibition of Glucocorticoid Receptor Synergistic Activity Depends on Stable Assembly at the Promoter but not on DAXX. Molecular endocrinology. 2008;22(9):2061-75.

  6. Evelyn CR, Wade SM, Wang Q, Wu M, Iñiguez-Lluhí JA, Merajver SD, et al. CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling. Mol Cancer Ther. 2007;6(8):2249-60.

  7. Benson MD, Kieckhafer K, Li Q-J, Dudek D, Whorton MR, Sunahara RK, et al. SUMO modification regulates inactivation of the voltage-gated potassium channel Kv1.5. Proc Natl Acad Sci U S A. 2007;104(6):1805-10.

 

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