PGC-1-Related Coactivator, a Novel, Serum-Inducible Coactivator of Nuclear Respiratory Factor 1-Dependent Transcription in Mammalian Cells

Abstract

The thermogenic peroxisome proliferator-activated receptor ␥ (PPAR-␥) coactivator 1 (PGC-1) has previously been shown to activate mitochondrial biogenesis in part through a direct interaction with nuclear respiratory factor 1 (NRF-1). In order to identify related coactivators that act through NRF-1, we searched the databases for sequences with similarities to PGC-1. Here, we describe the first characterization of a 177-kDa transcriptional coactivator, designated PGC-1-related coactivator (PRC). PRC is ubiquitously expressed in murine and human tissues and cell lines; but unlike PGC-1, PRC was not dramatically up-regulated during thermogenesis in brown fat. However, its expression was down-regulated in quiescent BALB/3T3 cells and was rapidly induced by reintroduction of serum, conditions where PGC-1 was not detected. PRC activated NRF-1-dependent promoters in a manner similar to that observed for PGC-1. Moreover, NRF-1 was immunoprecipitated from cell extracts by antibodies directed against PRC, and both proteins were colocalized to the nucleoplasm by confocal laser scanning microscopy. PRC interacts in vitro with the NRF-1 DNA binding domain through two distinct recognition motifs that are separated by an unstructured proline-rich region. PRC also contains a potent transcriptional activation domain in its amino terminus adjacent to an LXXLL motif. The spatial arrangement of these functional domains coincides with those found in PGC-1, supporting the conclusion that PRC and PGC-1 are structurally and functionally related. We conclude that PRC is a functional relative of PGC-1 that operates through NRF-1 and possibly other activators in response to proliferative signals.Nuclear respiratory factor 1 (NRF-1) was originally identified as a nuclear transcription factor that trans-activates the promoters of a number of mitochondrion-related genes in vitro (5, 9,10, 31). These include respiratory subunits and the ratelimiting heme biosynthetic enzyme, as well as factors involved in the replication and transcription of mitochondrial DNA (reviewed in reference 25). In addition to its proposed role in respiratory chain expression, NRF-1 has also been implicated in other cellular functions. Most recently, genes encoding two rate-limiting enzymes in purine nucleotide biosynthesis (6), a receptor involved in chemokine signal transduction (32), a subunit of a neural receptor (20), and the human polio virus receptor CD155 (27) were all shown to have functional NRF-1 binding sites in their promoters. Moreover, we recently established that targeted disruption of the NRF-1 gene in mice results in early embryonic lethality associated with a deficiency in mitochondrial DNA (15). These observations are consistent with a broad role for NRF-1 in growth and development.

Possible role for avPGC‐1α in the control of expression of fiber type, along with avUCP and avANT mRNAs in the skeletal muscles of cold‐exposed chickens

“…PGC-1a was originally cloned from brown adipose tissue on the basis of its interaction with PPARc [1]. The avPGC1a cloned here from chicken skeletal muscle, unlike the subfamily of PGC-1a, PGC-1b [28] or PGC-1-related coactivator (PRC) [29], includes motifs specific to PGC-1a in similar positions as described in the following ( Fig. 2A): An activation domain, including the LXXLL motif (aa 142-146), which is common to PRC, and three consensus sites for phosphorylation by protein kinase A (aa 237-240, 371-375, and 653-656) are well conserved; in contrast the arginine of codon 173 and the alanine of codon 329 in the mouse and rat PGC-1a are deleted in bird.…”

Increased mitochondrial biogenesis in primary leukemia cells: the role of endogenous nitric oxide and impact on sensitivity to fludarabine

“…Alterations in the expression of all three of these factors have been shown to modulate mitochondrial biogenesis activity. 19,[22][23][24] RT-PCR analyses revealed that the expression of NRF-1 and TFAM was markedly higher in the majority (eight of 10) CLL patients as compared to the normal lymphocytes, whereas the expression of PRC appeared unchanged in all cases (Figure 2b). Considering that NRF-1 activates the transcription of TFAM, it is not surprising that TFAM expression would also be elevated in cells with higher basal NRF-1 expression.…”

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…PGC-1s: meet the parents PGC-1α was first identified in a yeast two-hybrid screen for factors that interact with the nuclear receptor PPARγ in brown adipose tissue (BAT) in the context of cold-induced thermogenesis [1]. Soon after, two homologous genes, PGC-1β [6] and PRC [7] were cloned by cDNA and protein sequence homology, respectively. Although these proteins are encoded by different genes, their modular structure is remarkably similar [8], which explains the partial overlap in their physiological roles [3].…”