Ronald Cohen, M.D.

Role of Corepressor Action with Nuclear Hormone Receptors

Research Summary

The overall goal of my research is to study the role of nuclear corepressors in hormone action. The thyroid hormone (TR) and retinoic acid (RAR) receptors bind the nuclear corepressors, including NCoR (nuclear corepressor protein) and SMRT (silencing mediator for retinoid and thyroid hormone receptors), in the absence of their respective ligands. NCoR and SMRT contain C-terminal interaction domains (IDs) containing the consensus sequence I/L-x-x-I/V-I (CoRNR box). Our work has demonstrated that TRb1 preferentially interacts with NCoR, whereas RARa prefers SMRT. This is due to the preferential interactions of the proximal IDs within NCoR and SMRT. We have also demonstrated that this preference is due, in part, to the presence of a unique domain in NCoR, not present in SMRT; this domain is specific for TR and does not bind RAR. Our data also suggests that the presence of two interacting domains is necessary for full interactions with nuclear receptors in cells. In addition, while the exact CoRNR box sequence of the SMRT ID is critical for recruitment of SMRT by RAR, the CoRNR box sequences themselves do not explain the strong interactions of the NCoR N2 domain with TR. Further studies will evaluate additional regions needed for optimal binding.

The specific roles of corepressors and nuclear hormone receptors in the pituitary and pancreas are also studied. Hesx1 is a repressing protein that binds the corepressors NCoR and TLE1 and is vital for pituitary development. We are studying a patient with growth hormone deficiency and septo-optic dysplasia caused by a mutation in Hesx1. This leads to abnormal regulation of repression in the developing pituitary. The mechanisms underlying such abnormalities are being investigated. Finally, studies evaluating the roles of nuclear corepressors in the adipocyte are being initiated.

Selected Papers

Hashimoto K, Curty FH, Borges PP, Lee CE, Abel ED, Elmquist JK, Cohen RN, Wondisford FE. (2001). The unliganded thyroid hormone receptor causes severe neurological dysfunction. Proc Natl Acad Sci U S A 98:3998-4003.

Cohen RN, Brzostek S, Kim B, Chorev M, Wondisford FE, Hollenberg AN. (2001). The specificity of interactions between nuclear hormone receptors and corepressors is mediated by distinct amino acid sequences within the interacting domains. Mol. Endocrinol. 15:1049-1061.

Pohlenz J, Dumitrescu A, Zundel D, Martine U, Schonberger W, Koo E, Weiss RE, Cohen RN, Kimura S, Refetoff S. (2002). Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in human and mice. J Clin Invest. 109: 469-473.

Makowski A, Brzostek S, Cohen RN, Hollenberg AN. (2003). Determination of nuclear receptor corepressor interactions with the thyroid hormone receptor. Mol Endocrinol. 17: 273-286.

Shibusawa N, Hashimoto K, Nikrodhanond AA, Liberman MC, Applebury ML, Liao XH, Robbins JT, Refetoff S, Cohen RN, Wondisford FE. (2003). Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo. J Clin Invest. 112: 588-597.

Cohen RN, Cohen LE, Botero D, Yu C, Sagar A, Jurkiewicz M, Radovick S. (2003). Enhanced repression by HESX1 as a cause of hypopituitarism and septo-optic dysplasia. J Clin Endocrinol Metab. 88: 4832-4839.

Ortiga-Carvalho TM, Hashimoto K, Pazos-Moura CC, Geenen D, Cohen RN, Lang RM, Wondisford FE. (2004). Thyroid hormone resistance in the heart: role of the thyroid hormone receptor beta isoform. Endocrinology. Apr;145(4):1625-33.