Nuclear Hormone Receptor Coregulator: Role in Hormone Action, Metabolism, Growth, and Development
Muktar A. Mahajan and
Herbert H. Samuels
Departments of Pharmacology and Medicine, New York University School of Medicine, New York, New York 10016
Correspondence: Address all correspondence and requests for reprints to: Herbert H. Samuels, M.D., or Muktar Mahajan, Ph.D., Departments of Pharmacology and Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016. E-mail: herbert.samuels{at}med.nyu.edu, or muktar.mahajan{at}med.nyu.edu
Nuclear hormone receptor coregulator (NRC) (also referred toas activating signal cointegrator-2, thyroid hormone receptor-bindingprotein, peroxisome proliferator activating receptor-interactingprotein, and 250-kDa receptor associated protein) belongs toa growing class of nuclear cofactors widely known as coregulatorsor coactivators that are necessary for transcriptional activationof target genes. The NRC gene is also amplified and overexpressedin breast, colon, and lung cancers. NRC is a 2063-amino acidprotein that harbors a potent N-terminal activation domain (AD1)and a second more centrally located activation domain (AD2)that is rich in Glu and Pro. Near AD2 is a receptor-interactingdomain containing an LxxLL motif (LxxLL-1), which interactswith a wide variety of ligand-bound nuclear hormone receptorswith high affinity. A second LxxLL motif (LxxLL-2) located inthe C-terminal region of NRC is more restricted in its nuclearhormone receptor specificity. The intrinsic activation potentialof NRC is regulated by a C-terminal serine, threonine, leucine-regulatorydomain. The potential role of NRC as a cointegrator is suggestedby its ability to enhance transcriptional activation of a widevariety of transcription factors and from its in vivo associationwith a number of known transcriptional regulators includingCBP/p300. Recent studies in mice indicate that deletion of bothNRC alleles leads to embryonic lethality resulting from generalgrowth retardation coupled with developmental defects in theheart, liver, brain, and placenta. NRC–/– mouseembryo fibroblasts spontaneously undergo apoptosis, indicatingthe importance of NRC as a prosurvival and antiapoptotic gene.Studies with 129S6 NRC+/– mice indicate that NRC is apleiotropic regulator that is involved in growth, development,reproduction, metabolism, and wound healing.
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