Tumor suppressor p53 and estrogen receptors in nuclear-mitochondrial communication

Abstract

Several gene transcription regulators considered solely localized within the nuclear compartment are being reported to be present in the mitochondria as well. There is growing interest in the role of mitochondria in regulating cellular metabolism in normal and disease states. Various findings demonstrate the importance of crosstalk between nuclear and mitochondrial genomes, transcriptomes, and proteomes in regulating cellular functions. Both tumor suppressor p53 and estrogen receptor (ER) were originally characterized as nuclear transcription factors. In addition to their individual roles as regulators of various genes, these two proteins interact resulting in major cellular consequences. In addition to its nuclear role, p53 has been localized to the mitochondria where it executes various transcription-independent functions. Likewise, ERs are reported to be present in mitochondria; however their functional roles remain to be clearly defined. In this review, we provide an integrated view of the current knowledge of nuclear and mitochondrial p53 and ERs and how it relates to normal and pathological physiology.

Keywords: breast cancer; estrogen receptor; metabolism; mitochondria; p53.

Fig: 1. Schematic representation of p53-medicated functions in glucose metabolism, mitochondrial respiration, mitochondrial homeostasis and cell death

p53 is able to transcriptionally repress glucose transporters GLUT1 and GLUT4 along with the insulin receptor (IR) to inhibit cellular glucose uptake in to the cell. Through transcriptional activation of TP53-induced glycolysis and apoptosis regulator (TIGAR), p53 decreases the rate of glycolysis and redirect glycolytic intermediates into the pentose phosphate pathway (PPP). Glycolysis is also dampened by negative regulation of phosphoglycerate mutase (PGM) by p53. In contrast, transcriptional activation of hexokinase II (HK II) by mutant p53 stimulates glycolysis. The mitochondrion is the site of ATP generation via the tricarboxylic acid (TCA) cycle and the electron-transport chain (ETC). p53 promotes oxidative phosphorylation (OXPHOS) through transcriptional activation of synthesis of cytochrome c oxidase 2 (SCO2), a regulator of complex IV and apoptosis-inducing factor (AIF) that acts directly on complex 1. By regulating transcription and stability of ribonucleotide reductase subunit (p53R2), p53 maintains mitochondrial homeostasis and mitochondrial genome integrity. p53 is able to transcriptionally regulate and interact with the nuclear encoded mitochondrial transcription factor A (TFAM) and play a role in mitochondrial DNA (mtDNA) transcription and in regulating mtDNA content. Genotoxic stress signals trigger cytoplasmic p53 to undergo MDM2-dependent mono-ubiquitination that induces translocation of p53 to the mitochondria. P53 is then deubiquitinated by herpesvirus-associated ubiquitin-specific protease (HAUSP), which generates a mitochondrially-restricted, apoptotically capable pool of p53 protein. Mitochondrial p53 has been shown to interact and inhibit anti-apoptotic members of the Bcl-2 protein family and can directly trigger apoptosis by interacting with Bax and Bcl-xL. Combined role of transcriptional and mitochondrial functions of p53 in regulating apoptosis is evident in involvement of Bcl-x_L, PUMA, and NOXA. Mitochondrial p53 has been demonstrated to block the antioxidant function of manganese superoxide dismutase (MnSOD). Role of p53 in regulating metabolic pathways is an emerging rapidly moving area of research, and the influence of p53 on metabolism is likely to be much more complex than illustrated here.

Fig 2. Schematic representation of ER signaling in glucose metabolism and mitochondrial respiration

ERα activated by E2 controls gene expression in the nucleus by binding to EREs in target gene promoters followed by recruitment of coactivator complexes (COAC1, COAC2, COAC3) leading to transcriptional activation. Genes activated by ERα include those that encode proteins involved in mitochondrial biogenesis such as nuclear respiratory factors (NRF1) and still unknown metabolic proteins and enzymes that may participate in various pathways (as indicated by black broken arrows) regulating glycolysis and oxidative phosphorylation (OXPHOS). The mitochondrial localized transcription machinery (mt-TM) and TFAM are encoded in the nucleus and their expression is controlled by ERα and NRF-1. E2 dependent increased transcription and protein expression of NRF-1 induces mitochondrial biogenesis. Both ERα and ERβ are reported to modulate insulin signaling and glucose uptake. When Insulin signaling is activated, numerous proteins are phosphorylated leading to the translocation of GLUT4-containing vesicles to the cell membrane, where GLUT4 facilities the glucose uptake into the cell. ERα modulates GLUT4 transcription and translocation to the cell membrane and glucose uptake, while ERβ is a repressor of GLUT4 expression. The presence of both ERs in mitochondria in many mammalian tissues and cell lines has been reported, but remains controversial. The question mark indicates an experimentally unresolved observation.

Fig 3. Hypothetical model for ER-mediated antagonism of p53 function in a tumor cell

In tumor cells ERs participate in activating insulin signaling that leads to the translocation of GLUT4-containing vesicles to the cell membrane where GLUT4 enables the entry of glucose to increase the rate of aerobic glycolysis (“Warburg effect”). Tumor cells largely convert most of the glucose to lactate via less efficient aerobic glycolysis that results in minimal ATP production. In breast cancer cells, ER has been reported to bind and inhibit wild type p53 function in the nucleus. In a tumor cell, ERs may promote establishing a prominent glycolytic profile by repressing p53-mediated enhancement of mitochondrial oxidative phosphorylation and transcription of antiproliferative gene networks. Likewise, ERs may repress genes regulated by p53 that are vital to mitochondrial hemostasis and genome integrity. Accumulating mtDNA damage will ultimately lead to the impairment of oxidative phosphorylation (OXPHOS). Impaired OXPHOS is reported to cause further genomic and mtDNA instability, decreased apoptosis, and a cellular environment indicative of the Warburg effect. Overall this model suggests that in a cancer cell, ER is able to negatively affect mitochondrial p53 function, leading to altered metabolic profile and tumorigenesis.