We report here the identification of a novel cofactor, ACTR, that directly binds nuclear receptors and stimulates their transcriptional activities in a hormone-dependent fashion. ACTR also recruits two other nuclear factors, CBP and P/CAF, and thus plays a central role in creating a multisubunit coactivator complex. In addition, and unexpectedly, we show that purified ACTR is a potent histone acetyltransferase and appears to define a distinct evolutionary branch to this recently described family. Thus, hormonal activation by nuclear receptors involves the mutual recruitment of at least three classes of histone acetyltransferases that may act cooperatively as an enzymatic unit to reverse the effects of histone deacetylase shown to be part of the nuclear receptor corepressor complex.

Nuclear receptors (also known as nuclear hormone receptors) are hormone-regulated transcription factors that control many important physiological and developmental processes in animals and humans. Defects in receptor function result in disease. The diverse biological roles of these receptors reflect their surprisingly versatile transcriptional properties, with many receptors possessing the ability to both repress and activate target gene expression. These bipolar transcriptional properties are mediated through the interactions of the receptors with two distinct classes of auxiliary proteins: corepressors and coactivators. This review focuses on how corepressors work together with nuclear receptors to repress gene transcription in the normal organism and on the aberrations in this process that lead to neoplasia and endocrine disorders. The actions of coactivators and the contributions of the same corepressors to the functions of nonreceptor transcription factors are also touched on.

Retinoic acid receptors (RARs) are hormone-regulated transcription factors that control key aspects of normal differentiation. Aberrant RAR activity may be a causal factor in neoplasia. Human acute promyelocytic leukemia, for example, is tightly linked to chromosomal translocations that fuse novel amino acid sequences (denoted PML, PLZF, and NPM) to the DNA-binding and hormone-binding domains of RAR␣. The resulting chimeric receptors have unique transcriptional properties that may contribute to leukemogenesis. Normal RARs repress gene transcription by associating with ancillary factors denoted corepressors (also referred to as SMRT, N-CoR, TRAC, or RIP13). We report here that the PML-RAR␣ and PLZF-RAR␣ oncoproteins retain the ability of RAR␣ to associate with corepressors, and that this corepressor association correlates with certain aspects of the leukemic phenotype. Unexpectedly, the PLZF moiety itself can interact with SMRT corepressor. This interaction with corepressor is mediated, in part, by a POZ motif within PLZF. Given the presence of POZ motifs in a number of known transcriptional repressors, similar interactions with SMRT may play a role in transcriptional silencing by a variety of both receptor and nonreceptor transcription factors.Retinoids regulate many aspects of vertebrate cell proliferation and differentiation through receptors that function as hormone-regulated transcription factors (1-6). Two major classes of retinoid receptors have been identified: retinoic acid receptors (RARs) and retinoid X receptors (RXRs) (3-6). Both RARs and RXRs bind to specific sites on the DNA, and they can activate or repress expression of adjacent target genes (1-6). Aberrant RARs appear to play a crucial role in human acute promyelocytic leukemia (APL) (7-15). In over 95% of all APL patients, specific chromosomal translocations create abnormal RARs by replacing the N terminus of RAR␣ with novel ORFs. The breakpoint in RAR␣ is identical in all cases, whereas the nature of the novel N-terminal sequences can vary. In the common t(15;17) translocation, the RAR␣ N terminus is replaced with an ORF denoted PML (for promyelocytic leukemia) (7-12). Alternatively, t(11;17) and t(5;17) translocations result in chimeric proteins denoted PLZF (promyelocytic leukemia zinc finger)-RAR␣ and NPM (nucleophosmin)-RAR␣, respectively (13-15). Although possessing a number of recognizable structural motifs, including several prevalent in transcription factors, the PML, PLZF, and NPMderived sequences exhibit little structural interrelatedness, and the functions of these proteins in the normal cell are not fully understood (reviewed in refs. 16-18).The near-invariant association of acute promyelocytic leukemia with the expression of chimeric RAR␣ proteins, and the ability of retinoids to drive leukemias bearing the PML-RAR␣ translocation into differentiation and clinical remission (16-18), suggest an active role for these chimeras in conferring the leukemogenic phenotype. Furthermore, ectopic expression of PML-RAR␣ in murine or av...

For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects, leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is known about the mechanisms by which THs increase oxidative metabolism. Here, we report that TH stimulation of fatty acid β-oxidation is coupled with induction of hepatic autophagy to deliver fatty acids to mitochondria in cell culture and in vivo. Furthermore, blockade of autophagy by autophagy-related 5 (ATG5) siRNA markedly decreased TH-mediated fatty acid β-oxidation in cell culture and in vivo. Consistent with this model, autophagy was altered in livers of mice expressing a mutant TR that causes resistance to the actions of TH as well as in mice with mutant nuclear receptor corepressor (NCoR). These results demonstrate that THs can regulate lipid homeostasis via autophagy and help to explain how THs increase oxidative metabolism. IntroductionThyroid hormones (THs) have been known to stimulate basal metabolic rate for over a century (1, 2). Subsequent studies showed that THs induced energy expenditure in response to increased caloric intake (3). Later, several intracellular processes were shown to be involved in the calorigenic effects of THs. These included increased ATP expenditure due to increased Na + /K + -ATPase activity to maintain ion gradients in various tissues (4, 5) as well as reduced efficiency of ATP synthesis, particularly through the induction of uncoupling proteins (UCPs), which cause proton leakage in the electron transport chain of the mitochondria of target tissues (6, 7). However, despite these advances in our understanding of THs on cellular metabolism, none of these proposed mechanisms appears to be dominant. Currently, little is known about other mechanisms that might be utilized by THs to regulate energy consumption within the cell. This is particularly true for the events involved in the delivery of fatty acids to mitochondria, a necessary step in converting stored intracellular triglyceride fuel into ATP.The active form of TH, 3,3′5-triiodo-l-thyronine (T 3 ), is a critical regulator of cellular and tissue metabolism throughout the body. It controls gene expression in target tissues by binding to its cognate nuclear receptors (TRα and TRβ), which are ligand-inducible transcription factors. In the presence of T 3 , TH receptors (TRs) bind to TH response elements in the promoters of target genes and form coactivator complexes containing histone acetyltransferase activity to activate transcription (8). In the absence of T 3 , TRs recruit corepressors such as NCoR and silencing mediator of retinoid and thyroid receptors (SMRT), which together with transducin β-like protein 1 (TBL1) and histone deacetylase 3 (HDAC3)