News and Publications

Molecular Mechanisms That Confer Specificity to Nuclear Receptor Signaling

Steroid hormones play important roles in mammalian physiology and have widespread applications as drugs. These hormones exert their effects by binding and activating nuclear receptors that are ligand-regulated transcription factors. The responses elicited by the activated receptors are remarkably cell-type specific and dependent on the physiologic state of the organism. Thus, receptors for steroids are an ideal model system for studying the mechanisms that confer specificity and versatility to signaling pathways. We focus on receptor cofactors that we identified as modulators of steroid signaling and that confer specificity and/or regulation. Understanding the mechanism of action of these cofactors may reveal novel interventions for activating, suppressing, or altering the specificity of hormone action.

Glucocorticoids and Response to Stress

The ability of organisms to respond and adapt to stressors is fundamental for life. Response to stress involves activation of the neuroendocrine system and the secretion of adrenal glucocorticoids. Glucocorticoids act via the glucocorticoid receptor to enable mobilization of energy resources, recovery from the stress response, and preparation for future stressors. The transcriptional response mediated by receptors for glucocorticoids integrates the hormonal signal with signals indicating the type of stressor, the physiologic state of the organism, and the cellular environment. Our aim is to elucidate the molecular mechanisms and regulatory networks that enable the integration of such diverse signals in the activity of glucocorticoid receptors. In particular, we address the functions of coactivators, such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1), as integrators of such responses. PGC-1, an inducible coactivator that may coordinate transcriptional programs important for energy homeostasis, is a potent, tissue-specific modulator of glucocorticoid receptors. To elucidate the role of PGC-1 in glucocorticoid signaling, we examined the domains and functions of the coactivator that are required for enhancement of activity of glucocorticoid receptors and identified proteins that interact with these domains and may regulate or mediate PGC-1 functions. One of these proteins is the estrogen-related receptor α, an orphan nuclear receptor whose physiologic role is poorly understood. Our studies suggest that a regulatory network of PGC-1, estrogen-related receptor α, and glucocorticoid receptor coordinates part of the stress response. Our aim is to understand the underlying molecular mechanisms and the physiologic role of these interactions.

PGC-1­Related Estrogen Receptor Coactivator, a Modulator of Estrogen Responses

PGC-1 is the first identified member of a family of sequence-related coactivators. In contrast to PGC-1, which modulates the activity of most nuclear receptors, a homolog, PGC-1-related estrogen receptor coactivator (PERC) enhances selectively the activity of the estrogen receptor α. Depending on the promoter and cellular context, PGC-1 and PERC differ in their abililties to enhance the activity of estrogen receptor α, suggesting that the 2 coactivators have distinct functions in estrogen signaling. Currently, we are elucidating the physiologic functions of PERC in the actions of estrogen.

Publications

Emter, R., Heese-Peck, A., Kralli, A. ERG6 and PDR5 regulate small lipophilic drug accumulation in yeast cells via distinct mechanisms. FEBS Lett. 521:57, 2002.

Kressler, D., Schreiber, S.N., Knutti, D., Kralli A. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor α. J. Biol. Chem. 277:13918, 2002.

Schreiber, S.N., Knutti, D., Brogli, K., Uhlmann, T., Kralli, A. The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor α (ERRα). J. Biol. Chem. 278:9013, 2003.