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- 저자 : Puigserver, Pere (검색결과 4 건)
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A PGC1α-mediated transcriptional axis suppresses melanoma metastasis
Luo, Chi,Lim, Ji-Hong,Lee, Yoonjin,Granter, Scott R.,Thomas, Ajith,Vazquez, Francisca,Widlund, Hans R.,Puigserver, Pere Nature Publishing Group 2016 Nature Vol. No.
<P>Melanoma is the deadliest form of commonly encountered skin cancer because of its rapid progression towards metastasis(1,2). Although metabolic reprogramming is tightly associated with tumour progression, the effect of metabolic regulatory circuits on metastatic processes is poorly understood. PGC1 alpha is a transcriptional coactivator that promotes mitochondrial biogenesis, protects against oxidative stress(3) and reprograms melanoma metabolism to influence drug sensitivity and survival(4,5). Here, we provide data indicating that PGC1 alpha suppresses melanoma metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1 alpha expression inversely correlates with vertical growth in human melanoma specimens. PGC1 alpha silencing makes poorly metastatic melanoma cells highly invasive and, conversely, PGC1 alpha reconstitution suppresses metastasis. Within populations of melanoma cells, there is a marked heterogeneity in PGC1 alpha levels, which predicts their inherent high or low metastatic capacity. Mechanistically, PGC1 alpha directly increases transcription of ID2, which in turn binds to and inactivates the transcription factor TCF4. Inactive TCF4 causes downregulation of metastasis-related genes, including integrins that are known to influence invasion and metastasis(6-8). Inhibition of BRAF(V600E) using vemurafenib(9), independently of its cytostatic effects, suppresses metastasis by acting on the PGC1 alpha-ID2-TCF4-integrin axis. Together, our findings reveal that PGC1 alpha maintains mitochondrial energetic metabolism and suppresses metastasis through direct regulation of parallel acting transcriptional programs. Consequently, components of these circuits define new therapeutic opportunities that may help to curb melanoma metastasis.</P>
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Oh, Kyoung-Jin,Park, Jinyoung,Kim, Su Sung,Oh, Hyunhee,Choi, Cheol Soo,Koo, Seung-Hoi,Puigserver, Pere Public Library of Science 2012 PLoS genetics Vol.8 No.9
<▼1><P>Peripheral insulin resistance contributes to the development of type 2 diabetes. TCF7L2 has been tightly associated with this disease, although the exact mechanism was largely elusive. Here we propose a novel role of TCF7L2 in hepatic glucose metabolism in mammals. Expression of medium and short isoforms of TCF7L2 was greatly diminished in livers of diet-induced and genetic mouse models of insulin resistance, prompting us to delineate the functional role of these isoforms in hepatic glucose metabolism. Knockdown of hepatic TCF7L2 promoted increased blood glucose levels and glucose intolerance with increased gluconeogenic gene expression in wild-type mice, in accordance with the PCR array data showing that only the gluconeogenic pathway is specifically up-regulated upon depletion of hepatic TCF7L2. Conversely, overexpression of a nuclear isoform of TCF7L2 in high-fat diet-fed mice ameliorated hyperglycemia with improved glucose tolerance, suggesting a role of this factor in hepatic glucose metabolism. Indeed, we observed a binding of TCF7L2 to promoters of gluconeogenic genes; and expression of TCF7L2 inhibited adjacent promoter occupancies of CREB, CRTC2, and FoxO1, critical transcriptional modules in hepatic gluconeogenesis, to disrupt target gene transcription. Finally, haploinsufficiency of TCF7L2 in mice displayed higher glucose levels and impaired glucose tolerance, which were rescued by hepatic expression of a nuclear isoform of TCF7L2 at the physiological level. Collectively, these data suggest a crucial role of TCF7L2 in hepatic glucose metabolism; reduced hepatic expression of nuclear isoforms of this factor might be a critical instigator of hyperglycemia in type 2 diabetes.</P></▼1><▼2><P><B>Author Summary</B></P><P>Previous genome-wide association studies revealed that TCF7L2 is a strong candidate for a type 2 diabetes gene. However, the direct involvement of TCF7L2 on hepatic glucose metabolism has been elusive to date. Here we show that TCF7L2 is critical in mediating transcriptional control of hepatic glucose production. We found that hepatic expression of nuclear isoforms of TCF7L2 was reduced in mouse models of insulin resistance. Acute depletion of TCF7L2 in the liver promoted glucose intolerance and up-regulation of gluconeogenic genes, while ectopic expression of TCF7L2 in DIO mice improved glucose tolerance. TCF7L2 was shown to bind to the gluconeogenic promoters, thereby interfering with the promoter occupancies of both CREB/CRTC2 and FoxO1 on their cognate sites. Furthermore, TCF7L2 haploinsufficiency promoted higher glucose levels with impaired glucose tolerance and increased hepatic glucose production in mice, and adenovirus-mediated TCF7L2 expression in the liver reversed the phenotype. We propose that TCF7L2 is a critical player in regulating glucose homeostasis in mammals by modulating hepatic glucose production.</P></▼2>
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Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism
Pan, Youdong,Tian, Tian,Park, Chang Ook,Lofftus, Serena Y.,Mei, Shenglin,Liu, Xing,Luo, Chi,O’Malley, John T.,Gehad, Ahmed,Teague, Jessica E.,Divito, Sherrie J.,Fuhlbrigge, Robert,Puigserver, Pere,Kru Macmillan Publishers Limited, part of Springer Nat 2017 Nature Vol.543 No.7644
Tissue-resident memory T (T<SUB>RM</SUB>) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of T<SUB>RM</SUB> cells are obscure. Here we show that mouse CD8<SUP>+</SUP> T<SUB>RM</SUB> cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8<SUP>+</SUP> T<SUB>RM</SUB> cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (T<SUB>CM</SUB>) cells in lymph nodes. In vitro, CD8<SUP>+</SUP> T<SUB>RM</SUB> cells, but not CD8<SUP>+</SUP> T<SUB>CM</SUB> cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8<SUP>+</SUP> T<SUB>RM</SUB> cells. The persistence of CD8<SUP>+</SUP> T<SUB>RM</SUB> cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo. Moreover, skin CD8<SUP>+</SUP> T<SUB>RM</SUB> cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8<SUP>+</SUP> T<SUB>RM</SUB> cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8<SUP>+</SUP> T<SUB>RM</SUB> cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8<SUP>+</SUP> T<SUB>RM</SUB> cells, and suggest that CD8<SUP>+</SUP> T<SUB>RM</SUB> cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.
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