Sci. Aging Knowl. Environ., 3 March 2004
Vol. 2004, Issue 9, p. pe9
[DOI: 10.1126/sageke.2004.9.pe9]

PERSPECTIVES

Regulation of Transcriptional Coactivator PGC-1{alpha}

Danielle Melloul, and Markus Stoffel

Danielle Melloul is in the Department of Endocrinology at Hadassah University Hospital, Jerusalem 91120, Israel. Markus Stoffel is in the Laboratory of Metabolic Diseases at Rockefeller University, New York, NY 10021, USA. E-mail: stoffel{at}mail.rockefeller.edu

http://sageke.sciencemag.org/cgi/content/full/2004/9/pe9

Key Words: nuclear receptor • metabolism • mitochondria • oxidative phosphorylation • type 2 diabetes

Introduction

The regulation of transcription in eukaryotic cells is a dynamic process that depends on chromatin structure and site-specific transcription factors (1, 2). Nuclear receptors are ligand-inducible transcription factors that regulate the expression of target genes involved in biological processes such as metabolism, development, and reproduction. For example, the peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function in many facets of lipid metabolism and have been implicated in pathological conditions related to this process, including atherosclerosis, obesity, and diabetes [reviewed in (3)] (see "Flipping Out" and "From Cheeseburgers to Chest Pains"). One of the PPARs, PPAR{gamma}, plays a pivotal role in fat cell differentiation and is a target of antidiabetic medications (see "Phosphate Fast"). Nuclear receptors and many other transcription factors recruit coregulators (coactivators or corepressors) and the basal transcription machinery to associate directly with RNA polymerase II and initiate gene-specific transcription. These coregulators are rate-limiting proteins that are essential for the regulated expression of target genes by nuclear receptors. They exert their effects through direct interaction with basal transcription factors and covalent modifications of histones and other transcriptional regulatory proteins (1, 2). Coregulator activity can be controlled by a variety of mechanisms including (i) nuclear/cytoplasmic translocation; (ii) posttranslational modifications such as phosphorylation, acetylation, and methylation; and (iii) regulated proteolysis (4). Moreover, these coactivators or corepressors provide the capacity to integrate multiple regulatory inputs into a single tightly regulated transcriptional output. Results described in a recent paper by Fan et al. (5) provide new information about the control of one transcriptional coactivator, PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha}), which plays an important role in metabolic regulation and has been associated with type 2 diabetes.

Function and Expression of PGC-1{alpha}

PGC-1{alpha} was initially identified as a cold-inducible PPAR{gamma}-interacting protein from brown adipose tissue (which functions to produce heat), and was subsequently found to be associated with many other nuclear receptor proteins and transcription factors (6). This coactivator is expressed in a tissue-restricted manner, with higher concentrations in brown fat, heart, kidney, and skeletal muscle as compared to other tissues. It regulates multiple aspects of energy metabolism, most notably adaptive thermogenesis in brown adipose tissue, by stimulating mitochondrial biogenesis and mitochondrial oxidative metabolism, enabling adaptation to changes in metabolic demands. PGC-1{alpha} has also been implicated in heart development, in fiber type switching in skeletal muscle, and in regulation of the response to starvation in the liver, where PGC-1{alpha} promotes gluconeogenesis (the production of glucose from noncarbohydrate precursors) and glucose uptake [reviewed in (7)]. In these tissues, the expression of PGC-1{alpha} is highly regulated at the transcriptional level in response to environmental stimuli. For instance, cold exposure leads to a profound induction of PGC-1{alpha} gene expression in brown fat and skeletal muscle, which in turn triggers specific transcriptional programs resulting in enhanced mitochondrial biogenesis and expression of genes encoding uncoupling proteins (UCPs). UCPs dissipate the proton gradient across the inner mitochondrial membrane and thus uncouple electron transport from oxidative phosphorylation, leading to the stimulation of uncoupled mitochondrial respiration (see "Bouncer at the Energy Bar" and Nicholls Perspective. Physiological stimuli such as starvation can also act as potent inducers of PGC-1{alpha} gene expression in the liver through a mechanism that involves phosphorylation of the transcription factor cAMP response element-binding protein (8).

Posttranslational Regulation of PGC-1{alpha} Activity

Two previous studies by Spiegelman's and Kralli's groups have unveiled a posttranslational mechanism by which PGC-1{alpha} activity can be regulated. They demonstrate that PGC-1{alpha} contains a negative regulatory region that reduces the potency of the transcriptional activation domain located at the N terminus (9, 10). This inhibitory effect can be relieved via phosphorylation at three residues (Thr262, Ser265, and Thr298) (10) in the negative regulatory region of PGC-1{alpha} by a member of the mitogen-activated protein kinase (MAPK) family, p38 MAPK, which functions in the cellular response to stress. This kinase is activated by a variety of extracellular signals, including irradiation and proinflammatory cytokines [reviewed in (11)] (Fig. 1). These results thereby establish a pathway by which the activity of PGC-1{alpha} can be modified by extracellular signals.



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Fig. 1. Schematic drawing that illustrates the pathways that lead to the activation of p38 MAPK by growth factors, cytokines, or extracellular stress signals. p38 MAPK activation leads to the phosphorylation of transcriptional coactivator PGC-1{alpha}, thereby relieving it from the inhibitory action of p160MBP and activating target gene expression. Map 2K6, MAPK kinase 6; TF, transcription factor.

 
The recent work by Fan et al. (5) reveals further details about the molecular mechanism by which p38 MAPK activates PGC-1{alpha}. Using a biochemical affinity chromatography assay followed by mass spectrometry, the authors identified the p160 Myb binding protein (p160MBP) as an interacting partner of PGC-1{alpha}. These authors showed by cotransfection experiments in brown fat cells that p160MBP can suppress the ability of the full-length PGC-1{alpha} to activate transcription, but not that of a truncated PGC-1{alpha} coactivator form lacking the negative regulatory region (and therefore the p160MBP interacting domain). It was further shown by transfection experiments that the p160MPB protein can also repress transcription in the absence of PGC-1{alpha}, demonstrating its intrinsic transcriptional repressive activity. It seems that transcriptional repression by p160MBP is partly mediated through histone deacetylation, because the deacetylase inhibitor trichostatin diminishes the repressive activity of p160MBP in myoblasts.

Moreover, the authors show that p38 MAPK phosphorylation of PGC-1{alpha} disrupts the binding with p160MBP and repression of PGC-1{alpha} activity by p160MBP. Indeed, in cells treated with cytokines to induce the p38 MAPK-mediated phosphorylation of PGC-1{alpha}, significantly less interacting p160MBP was detected by immunoprecipitation as compared to the situation in cells not treated with cytokines. Furthermore, expression of MAPK kinase 6, the upstream activator of p38 MAPK, relieves the suppressive effect of p160MBP on PGC-1{alpha} activity. These findings were further confirmed by replacing the three phosphorylated residues (Thr262, Ser265, and Thr298) with aspartic acids to create a mutant version of PGC-1{alpha}, PGC1-3D. Because aspartate residues are negatively charged like phosphate groups, PGC1-3D mimics the phosphorylated state and activity of the protein. However, the PGC1-3D mutant protein fails to bind p160MBP and as a result is more resistant to repression by p160MBP than is PGC-1{alpha}.

Fan et al. also show that, whereas adenoviral-based expression of PGC-1{alpha} in myoblasts stimulates the expression of genes that encode components of the mitochondrial electron transport chain and results in increased mitochondrial respiration, the coexpression of p160MBP potently inhibits these effects. The authors use chromatin immunoprecipitation assays to show that PGC-1{alpha} is associated with the promoter of a PGC-1{alpha} target gene in these myoblasts. It is intriguing that the p160MBP-mediated repression does not require the removal of PGC-1{alpha} from chromatin, suggesting that p160MBP binds to PGC-1{alpha} on the DNA and directly represses its transcriptional activity (5).

PGC-1{alpha} and Diabetes

An understanding of how PGC-1{alpha} activity is regulated at the molecular level will be important to gain a deeper knowledge about mechanisms that contribute to energy homeostasis, cell differentiation, and aging, as well as pathological conditions such as diabetes. PGC-1{alpha} modulates gene expression that affects glucose and fat metabolism in a number of insulin-sensitive tissues. As discussed above, in muscle, PGC-1{alpha} expression leads to elevated levels of respiration and oxidative phosphorylation. In the liver, PGC-1{alpha} activates transcription factors that stimulate gluconeogenesis and glucose output. Increases in PGC-1{alpha} expression have been noted in the livers of insulin-resistant animal models as compared to their normal counterparts. More recently, two studies have reported that decreases in the amount of PGC-1{alpha} in skeletal muscle are associated with human type 2 diabetes and an increased risk of developing type 2 diabetes (12, 13). Individuals with this condition are insulin resistant; that is, their tissues do not respond normally to insulin and, as a result, serum concentrations of glucose can be much higher than normal.

Interestingly, the mechanism of PGC-1{alpha} repression by p160MBP and its relief by the cytokine/p38 MAPK signaling cascade might further explain these findings regarding PGC-1{alpha}'s role in the liver and skeletal muscle. Mice homozygous for the ob mutation exhibit obesity and insulin resistance and serve as a model for type 2 diabetes. p38 MAPK from livers of ob/ob diabetic mice displays increased constitutive phosphorylation relative to that of their ob/+ lean littermates (14). This result indicates that p38 MAPK might be highly effective in phosphorylating PGC-1{alpha} in the livers of the diabetic mice, thereby preventing the inhibitory actions of p160MBP and contributing to transcriptional activation of key enzymes of gluconeogenesis, such as phosphoenolpyruvate carboxykinase and the catalytic subunit of glucose-6-phosphatase (G6Pc). Transcription of the genes encoding these enzymes requires the transcription factors Foxo-1 and Hnf-4{alpha}, two transcriptional regulators that are implicated in the pathogenesis of type 2 diabetes and that have been shown to require the coactivator PGC-1{alpha} for full transcriptional activation.

In muscle, the role of p160MBP suppression of PGC-1{alpha} in the development of type 2 diabetes seems to be more complex. Decreased expression of PGC-1{alpha} in skeletal muscle has been associated with decreased oxidative phosporylation in type 2 diabetic patients, suggesting that decreased PGC-1{alpha} activity predisposes these individuals to impaired glucose and fat metabolism (12, 13). In contrast, increased levels of basal p38 MAPK phosporylation in skeletal muscle from type 2 diabetic patients (possibly mediated by the higher concentrations of circulating and tissue cytokines, such as tumor necrosis factor-{alpha}, in these patients relative to their healthy counterparts) would lead to an increase in p38 MAPK-dependent activation of PGC-1{alpha}, thereby compensating for its reduced expression levels (15). However, insulin exposure stimulates p38 MAPK phosphorylation in nondiabetic people but has no effect in the skeletal muscle of type 2 diabetic patients, suggesting that insulin resistance impairs activation of this pathway (16). This result might indicate that stimulation of p38 MAPK by insulin after a meal plays a role in activating genes of oxidative phosphorylation as well as enhancing insulin sensitivity and glucose metabolism, possibly by relieving the repression of PGC-1{alpha}. It is also worth mentioning that the p38 MAPK pathway is markedly induced by oxidative stress or chronic exposure to high glucose in pancreatic islets (insulin-secreting groups of cells within the pancreas) and that this induction precedes the reduction of insulin gene expression. Increased PGC-1{alpha} expression in pancreatic islets is associated with impaired function of pancreatic {beta} cells (which produce insulin), including the induction of G6Pc expression and suppression of expression of the glucose transporter Glut2 and glycolytic enzymes (17). Therefore, activation of PGC-1{alpha} by p38 MAPK might also play a functional role in the progressive {beta}-cell decompensation observed in insulin-resistant states. It may be noted here that studies exploring the function of PGC-1{alpha} so far have been conducted by increasing its expression in cells or tissues. It will be interesting in the future to study loss-of-function mutations in mice to help elucidate PGC-1{alpha}'s function in metabolism during normal and stress-induced conditions.

PGC-1{alpha}, Caloric Restriction, and Aging

Because of PGC-1{alpha}'s prominent role in mitochondrial mitogenesis and the induction of oxidative phosphorylation, it is tempting to speculate that PGC-1{alpha} might be involved in molecular mechanisms that link caloric restriction and aging processes. Calorie-restricted feeding retards the rate of aging in mammalian and invertebrate species (18) (see Masoro Subfield History). The mechanisms are incompletely understood, but there is growing evidence that the decline in aging-associated respiratory function can result in enhanced production of reactive oxygen species (ROS) in mitochondria. The accumulation of free radical-elicited oxidative damage is further promoted by the decline of the antioxidant system with age, leading to a gradual loss of prooxidant/antioxidant balance (see "The Two Faces of Oxygen"). As p38 MAPK phosphorylation (and thus activity) in muscle declines with age, it can be speculated that PGC-1{alpha}, which is a potent activator of transcription of the genes encoding UCP1, UCP2, and UCP3, protects cells from ROS production by uncoupling of oxidative phosphorylation (see "Bouncer at the Energy Bar"). For instance, higher levels of oxidative damage have been observed in mitochondria from UCP3-deficient mice as compared to mitochondria from wild-type controls, suggesting that UCP3 plays a role in vivo in antioxidative defense mechanisms (19). Induction of PGC-1{alpha} expression by caloric restriction might thus compensate for the loss of p38 MAPK activity, thereby maintaining the expression of UCPs and contributing to the protection against oxidative stress.

An extreme example linking PGC-1{alpha} expression and respiration and energy expenditure during calorie restriction is cachexia, a chronic state of negative energy balance during which respiration and energy expenditure are at a level that is inappropriately high for the nutritional state. The molecular pathogenesis of this condition is largely unknown, but it is clear that the concentrations of a broad spectrum of circulating cytokines are increased in cachexic patients, which leads to the activation of the p38 MAPK pathway. According to the study by Fan et al. (5), high concentrations of cytokines could lead to phosphorylation of PGC-1{alpha}, relieving it from the suppressive action of p160MBP and thereby promoting the transcription of genes associated with mitochondrial respiration and uncoupling. Thus, maximal PGC-1{alpha} activation by phosphorylation might contribute to extreme catabolism in muscle and the dysregulation of thermogenesis in cachexic patients.

Additional Roles for PGC-1{alpha}

Among the processes modulated by the p38 MAPK stress response pathways are differentiation and apoptosis. The biological responses to p38 MAPK activation are cell type- and differentiation-dependent. For instance, p38 MAPK activity is necessary for the differentiation of 3T3-L1 cultured fibroblasts into adipocytes; its activity is high during the initial stages of differentiation but decreases as these cells undergo terminal differentiation (20). This observation is consistent with a role of p38 MAPK in the activation of PGC-1{alpha} and PPAR{gamma}. However, constitutive activation of p38 MAPK in differentiated adipocytes leads to cell death, highlighting the importance of down-regulation of its activity in mature adipocytes for maintaining homeostasis. Although the p38 MAPK pathway has been linked to proliferation and apoptosis in many cell types, there is currently no experimental evidence that these effects could be mediated by activation of PGC-1{alpha}.

However, the identification of Cdc16 as an additional potential PGC-1{alpha}-interacting partner by Fan et al. (5) suggests that PGC-1{alpha} might be involved in functions involving cell cycle control and DNA replication. Cdc16 is a component of the anaphase-promoting complex, an E3 ubiquitin ligase (see Gray Review) required for cell cycle progression. In Saccharomyces cerevisiae, Cdc16 has recently been shown to negatively regulate DNA replication, suggesting that this protein could be important for normal chromosomal and mitochondrial DNA replication (21). Thus, if Cdc16, like p160MBP, acts as a suppressor of PGC-1{alpha} by binding to its inhibitory domain, it might also have a role in coupling cell growth and DNA replication to energy homeostasis in a cell. We look forward to more fascinating revelations of PGC-1{alpha}'s function and regulation.


March 3, 2004
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Citation: D. Melloul, M. Stoffel, Regulation of Transcriptional Coactivator PGC-1{alpha}. Sci. Aging Knowl. Environ. 2004 (9), pe9 (2004).




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