TFE3 and TFEB are broadly expressed transcription factors related to the transcription factor Mitf. Although they have been linked to cytokine signaling pathways in nonlymphoid cells, their function in T cells is unknown. TFE3-deficient mice are phenotypically normal, whereas TFEB deficiency causes early embryonic death. We now show that combined inactivation of TFE3 and TFEB in T cells resulted in a hyper-immunoglobulin M syndrome due to impaired expression of CD40 ligand by CD4 + T cells. Native TFE3 and TFEB bound to multiple cognate sites in the promoter of the gene encoding CD40 ligand (Cd40lg), and maximum Cd40lg promoter activity and gene expression required TFE3 or TFEB. Thus, TFE3 and TFEB are direct, physiological and mutually redundant activators of Cd40lg expression in activated CD4 + T cells critical for T cell-dependent antibody responses.Transcription factors TFE3 and TFEB are the most closely related members of a functionally interactive DNA-binding family known as Mitf-TFE (MiT) that includes the microphthalmiaassociated transcription factor Mitf and TFEC 1 . MiT proteins bind to μE3 sites, a subset of Eboxes that match a general CANNTG consensus sequence 2 , with those binding to TFE3 in vitro first identified and characterized in immunoglobulin heavy-chain and T cell receptor (TCR) enhancers 3-5 . DNA binding is mediated by nearly identical basic regions and requires homo-or heterodimer formation mediated by conserved helix-loop-helix and leucine zipper domains 5-7 . Such interactions are restricted in the MiT family.MiT proteins share similar structures and are often expressed together, yet genetic studies have demonstrated both overlapping and nonoverlapping functions for MiT proteins in different cell
Translocations of the genes encoding the related transcription factors TFE3 and TFEB are almost exclusively associated with a rare juvenile subset of renal cell carcinoma and lead to overexpression of TFE3 or TFEB protein sequences. A better understanding of how deregulated TFE3 and TFEB contribute to the transformation process requires elucidating more of the normal cellular processes in which they participate. Here we identify TFE3 and TFEB as cell type-specific leukemia inhibitory factor-responsive activators of E-cadherin. Overexpression of TFE3 or TFEB in 3T3 cells activated endogenous and reporter E-cadherin expression. Conversely, endogenous TFE3 and/or TFEB was required for endogenous E-cadherin expression in primary mouse embryonic fibroblasts and human embryonic kidney cells. Chromatin precipitation analyses and E-cadherin promoter reporter gene assays revealed that Ecadherin induction by TFE3 or TFEB was primarily or exclusively direct and mitogen-activated protein kinasedependent in those cell types. In mouse embryonic fibroblasts, TFE3 and TFEB activation of E-cadherin was responsive to leukemia inhibitory factor. In 3T3 cells, TFE3 and TFEB expression also induced expression of Wilms' tumor-1, another E-cadherin activator. In contrast, E-cadherin expression in model mouse and canine renal epithelial cell lines was indifferent to inhibition of endogenous TFE3 and/or TFEB and was reduced by TFE3 or TFEB overexpression. These results reveal new cell type-specific activities of TFE3 and TFEB which may be affected by their mutation.Deregulated expression of the related transcription factors TFE3 and TFEB is associated with rare, juvenile forms of the malignancy renal cell carcinoma (RCC), and TFE3 mutation with alveolar soft part sarcoma (for review, see Ref. 1). The genetic lesions are translocations that lead to dramatic overexpression of TFE3 or TFEB protein sequences. Five different genetic loci have been identified as translocation partners for TFE3, which lead to the creation of a chimeric protein containing the translocation partner at the N terminus fused to the C-terminal portion of TFE3 which includes its DNA binding and multimerization domains (1). TFEB translocations result in promoter substitution and do not change the coding sequence (2, 3). Although there is evidence that TFE3 fusion partners contribute oncogenic properties to the fusion protein (4, 5), TFEB overexpression in RCC 1 and the ability of normal TFE3 to promote clonotypic growth of melanoma cells suggest that overexpression of the TFE3 protein sequence is a critical oncogenic force (2). Moreover, TFE3, and to a lesser extent, TFEB, have been implicated in several cytokine signaling pathways that control cell growth and differentiation, but the precise mechanisms by which their dysregulation contributes to renal oncogenesis are not clear.TFE3 and TFEB are closely related members of the Mi/TFE3 (MiT) transcription factor family that includes TFEC and the microphthalmia (mi) transcription factor Mitf (6). TFE3 or TFEB overexpress...
With the introduction of netback deals negotiated in August 1985, the Saudis abdicated their role as the swing supplier to world oil markets. Their action ended 25 years in which first the international majors and then OPEC had held the line (officially) on crude prices at the expense of downstream margins. In 1986, oil price instability hit new highs, as sellers fought for market share in the absence of a "gatekeeper" on production and a marker crude reference price. Tranquility is not likely to be restored soon. Introduction In the early 1970s, oil belonged to the realm of the Seven Sisters—the international majors who produced most of the oil in the world outside communist areas (WOCA). Much of the oil flowed to end users through company-owned transport, refining, and marketing facilities. Company-controlled crude surplus to the major's requirements was supplied under long-term contracts to third-party (independent) refiners, particularly in Japan. The small amount of spot market (cargo-by-cargo) trading that did occur was mainly to correct short-term imbalances in refinery output of individual products. (Figure 1.) The Managed World Efforts to increase the volume of crude and product sales did create periods of price weakness. But in general, the majors acted as "gate- keepers" on production and balanced demand across different regions and market sectors. Their common interest in tuning crude supply to the requirements of the markets they served transcended national boundaries. They not only controlled much of the world's oil production through joint companies in Saudi Arabia, Iran, Iraq and elsewhere, the majors could draw from a constant flow of information needed to program supply from various sources. (Figure 2.) The companies' task was also facilitated by the growth in consumption as oil entered new markets and became the fuel of choice. For more than two decades (1950 to 1972), WOCA oil demand had been growing at a rapid, and fairly predictable, 7 percent per year. Consequently, integrated companies were concerned not so much to capture existing sales from a competitor as to ensure their own share of the growth. (Figure 3.) The result was that they managed to avoid destructive price competition. Nevertheless, it was during a period of competitive price weakness that OPEC was formed in September 1960, following a second cut in the posted price of Middle East crude to meet competition from other supplies. Concerned that their relationship with Middle East countries would deteriorate if further cuts were made, the majors made posted prices sacrosanct from then on. If downstream margins were squeezed by competitive pressures, the integrated companies simply maintained their postings and financed their operations out of profits from production. Clearly, posted prices create too strong an impression of stability during the 1960s and early 1970s, as shown in Table 1. Nevertheless, in the early years most of the oil which moved in international trade did so under long-term contracts at prices close to postings. It was not until the mid 1960s that the pressure of declining open market (spot) prices pushed contract prices below postings. From then on, posted prices were used solely to calculate oil company royalty and tax obligations. There was fairly uniform pricing for interaffiliate transactions. But third-party (contract and spot) prices were negotiated separately for individual customers, thereby differentiating among buyers and markets. This differentiation enabled the majors to balance crude supply and demand outside their own systems. P. 77^
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