Biological Control through Regulated Transcriptional Coactivators

Spiegelman, Bruce M.; Heinrich, Reinhart

doi:10.1016/j.cell.2004.09.037

Cited by 324 publications

(264 citation statements)

References 81 publications

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“…28 It is an open question whether the activation of these proteins by Yap1 recruits RNA polymerase II to interact with the general transcription apparatus 36 or whether Yap1 stabilizes the transcription factors. We cannot rule out the possibility that in fact Yap1 has a dual function.…”

Section: Discussionmentioning

confidence: 99%

The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73

et al. 2006

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Upon DNA damage signaling, p73, a member of the p53 tumor suppressor family, accumulates to support transcription of downstream apoptotic genes. p73 interacts with Yes-associated protein 1 (Yap1) through its PPPY motif, and increases p73 transactivation of apoptotic genes. The ubiquitin E3 ligase Itch, like Yap1, interacts with p73. Given the fact that both Itch and Yap1 bind p73 via the PPPY motif, we hypothesized that Yap may also function to stabilize p73 by displacing Itch binding to p73. We show that the interaction of Yap1 and p73 was necessary for p73 stabilization. Yap1 competed with Itch for binding to p73, and prevented Itch-mediated ubiquitination of p73. Treatment of cells with cisplatin leads to an increase in p73 accumulation and induction of apoptosis, but both were dramatically reduced in the presence of Yap1 siRNA. Altogether, our findings attribute a central role to Yap1 in regulating p73 accumulation and function under DNA damage signaling.

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Section: Discussionmentioning

confidence: 99%

The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73

et al. 2006

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“…Interestingly, one of the genes whose expression was significantly upregulated following TFEB overexpression was the peroxisome proliferator-activated receptor coactivator 1 (PGC1 ), a known key regulator of liver lipid metabolism that is transcriptionally induced during starvation 17,18 . To test whether PGC1 is a direct target of TFEB we analysed its promoter and identified three CLEAR sites.…”

Section: Tfeb Regulates Genes Involved In Lipid Metabolism Via Pgc1α mentioning

confidence: 99%

“…2c and Supplementary Table 7. These results strongly suggested that TFEB overexpression in fed mice phenocopied the transcriptional effects of nutrient deprivation in vivo, supporting the notion that TFEB is a critical regulator of the response to starvation in the liver.Interestingly, one of the genes whose expression was significantly upregulated following TFEB overexpression was the peroxisome proliferator-activated receptor coactivator 1 (PGC1 ), a known key regulator of liver lipid metabolism that is transcriptionally induced during starvation 17,18 . To test whether PGC1 is a direct target of TFEB we analysed its promoter and identified three CLEAR sites.…”

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confidence: 99%

Erratum: TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop

Settembre¹,

Cegli²,

Mansueto³

et al. 2013

Nat Cell Biol

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The lysosomal-autophagic pathway is activated by starvation and plays an important role in both cellular clearance and lipid catabolism. However, the transcriptional regulation of this pathway in response to metabolic cues is currently uncharacterized. Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via PGC1 and PPAR . Thus, during starvation a transcriptional mechanism links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the evolution of the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and * Correspondence to: Andrea Ballabio (ballabio@tigem.it) and Carmine Settembre (settembre@tigem.it). # These authors contributed equally and are listed in alphabetical order Supplementary Information is linked to the online version of the paper. www.nature.com/nature. Author Contributions C.S., G.M, P.K.S., F.V., O.V., T.H., R.DC., A.C., D.P., T.J.K, A.C.W. performed the experiments. D.d.B. supervised bioinformatic analyses. J.E.I supervised the C. elegans experiments, L.C supervised the metabolic studies, A.B. and C.S. designed the overall study and supervised the work. All authors discussed the results and made substantial contributions to the manuscript.The authors declare no competing financial interests. Readers are welcome to comment on the online version of this article at www.nature.com/nature. NIH Public Access Author ManuscriptNat Cell Biol. Author manuscript; available in PMC 2013 December 01. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a novel therapeutic strategy for disorders of lipid metabolism.The adaptive response of an organism to food deprivation is associated with major transcriptional and metabolic 1-5 changes and is conserved across evolution 6,7 . One of the most prominent metabolic changes observed during starvation is an increase in lipid catabolism in the liver.Autophagy, a lysosome-dependent catabolic process, is activated by starvation 8, and the resulting breakdown products are used to generate new cellular components and energy. Recent studies revealed that autophagy plays a central role in lipid metabolism since it shuttles lipid droplets to the lysosome where they are hydrolyzed into free fatty acids (FFAs) and glycerol 9,10 . Moreover, excessive lipid overload may inhibit autophagy, while enhancing liver autophagy in murine genetic models of obesity (Ob/Ob) ameliorates their metabolic phenotype 11 . These observations indicate the close relationship between intracellular lipid metabolism and the lysosomal-autophagic pathway. However, it is not clear how this relationship is coordinated at the transcriptional level in respo...

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“…In this regard, it is evident that the NRFs are responsible for the transcription of both nuclear and mtDNA. However, the mere binding of transcription factors to gene promoters do not activate gene transcription, nor does it imply transcriptional coordination between the nuclear and mitochondrial genomes (Spiegelman & Heinrich, 2004).…”

Section: Factors Involved In Mitochondrial Biogenesismentioning

confidence: 99%

PGC-1α Mediated Muscle Aerobic Adaptations to Exercise, Heat and Cold Exposure

Ihsan¹,

Watson²,

Abbiss³

2014

Cell Mol Exerc Physiol

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PGC-1α is regarded as a key regulator of mitochondrial biogenesis due to its central role in regulating the activity of key transcription factors associated with encoding mitochondrial components. Additionally, PGC-1α has shown to mediate adaptations that increase fat metabolism and angiogenesis, contributing to the overall oxidative phenotype of the muscle. While it is well established that exercise is a potent stimulator of PGC-1α, recent evidence indicates that heat and cold exposures may also influence mitochondrial biogenesis through the up-regulation of PGC-1α. This highlights the potential use of these modalities in conjunction with exercise to enhance training adaptations. As such, the purpose of this review is to describe the possible mechanisms and pathways by which exercise, as well as hot and cold exposures may influence mitochondrial biogenesis. It is clear that changes in intracellular calcium, oxidative stress and phosphorylation potential are major up-regulators of PGC-1α during exercise. Moreover, there is evidence implicating calcium signalling, in addition to β-adrenergic activation in cold-induced mitochondrial biogenesis, while PGC-1α during heat exposure is likely triggered by changes in phosphorylation potential and nitric oxide signalling. However, these mechanisms appear to change considerably when cold/heat is administered following exercise, and seem to be dependent on the experimental models used (i.e. in vitro vs. in vivo, rodent vs. human). Understanding the effects heat/cold exposure and its interaction with exercise may lead to the optimisation and development of temperature-related interventions to enhance training adaptations, or aid in the treatment of mitochondrial related diseases.

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Biological Control through Regulated Transcriptional Coactivators

Cited by 324 publications

References 81 publications

The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73

The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73

Erratum: TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop

PGC-1α Mediated Muscle Aerobic Adaptations to Exercise, Heat and Cold Exposure

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