TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling

The mammalian target of rapamycin (mTOR) pathway is commonly activated in human cancers. The activity of mTOR complex 1 (mTORC1) signaling is supported by the intracellular positioning of cellular compartments and vesicle trafficking, regulated by Rab GTPases. Here we showed that tuftelin 1 (TUFT1) was involved in the activation of mTORC1 through modulating the Rab GTPase-regulated process. TUFT1 promoted tumor growth and metastasis. Consistently, the expression of TUFT1 correlated with poor prognosis in lung, breast and gastric cancers. Mechanistically, TUFT1 physically interacted with RABGAP1, thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promoted mTORC1 signaling. In addition, expression of TUFT1 predicted sensitivity to perifosine, an alkylphospholipid that alters the composition of lipid rafts. Perifosine treatment altered the positioning and trafficking of cellular compartments to inhibit mTORC1. Our observations indicate that TUFT1 is a key regulator of the mTORC1 pathway and suggest that it is a promising therapeutic target or a biomarker for tumor progression.UTokyo FOCUS Articles掲載「がんの増殖・転移を促進する新規因子の同定 小胞輸送を標的とする新しいがん治療戦略への可能性」 https://www.u-tokyo.ac.jp/focus/ja/articles/z0508_00119.htmlUTokyo FOCUS Articles "Possible target for future cancer treatment : Deregulation of system to move molecules in the cell may promote tumor growth, metastasis" https://www.u-tokyo.ac.jp/focus/en/articles/z0508_00120.htm

Imbalanced expression of polycistronic miRNA in acute myeloid leukemia

miR-1 and miR-133 are clustered on the same chromosomal loci and are transcribed together as a single transcript that is positively regulated by ecotropic virus integration site-1 (EVI1). Previously, we described how miR-133 has anti-tumorigenic potential through repression of EVI1 expression. It has also been reported that miR-1 is oncogenic in the case of acute myeloid leukemia (AML). Here, we show that expression of miR-1 and miR-133, which have distinct functions, is differentially regulated between AML cell lines. Interestingly, the expression of miR-1 and EVI1, which binds to the promoter of the miR-1/miR-133 cluster, is correlative. The expression levels of TDP-43, an RNA-binding protein that has been reported to increase the expression, but inhibits the activity, of miR-1, were not correlated with expression levels of miR-1 in AML cells. Taken together, our observations raise the possibility that the balance of polycistronic miRNAs is regulated post-transcriptionally in a hierarchical manner possibly involving EVI1,suggesting that the deregulation of this balance may play some role in AML cells with high EVI1 expression

Systematic LREE enrichment of mantle harzburgites: The petrogenesis of San Carlos xenoliths revisited

The dichotomy between partial melting and metasomatism is a paradigm of mantle geochemistry since the pioneering work of Frey and Prinz (1978) on the occurrence of LREE-enriched harzburgites. However, the thermo-chemical implications of such two-stage scenarios are often poorly considered, and the latter fail to explain why trace-element enrichment and major-element depletion are often proportional. We here re-envisage the petrogenesis of the famous San Carlos peridotites based on new petrographic observations and detailed modal, major- and trace-element compositions. The lherzolites (and pyroxenites) are characterized by homogeneously fertile mineral chemistry and LREE-depleted patterns consistent with low degrees of partial melting of the lherzolitic protolith. Bulk compositions and mineral zoning suggest that opx-rich pyroxenites formed by pressure-solution creep during melt-present deformation, locally accompanied by magmatic segregations of cpx. The harzburgites are characterized by stronger mineral zoning with low-Mg# and Na-, Al- and Cr-rich cpx rims, and can be discriminated in a low-Jd and high-Jd cpx groups. The high-Jd group is interpreted as the result of local elemental redistribution in the presence of a low-degree hydrous melt, in good agreement with their wide range of LREE enrichment. In contrast, the MREE-to-HREE fractionation and increasing Cr# in spinel of the low-Jd group indicate that they experienced higher degrees of melting. Open-system melting simulations of trace-element fractionation during hydrous flux melting suggests that the high-Jd harzburgites are the result of low fluid influx producing poorly extracted melt, while higher influx led to higher melting degrees and efficient melt extraction in the low-Jd harzburgites; the lherzolites mostly remained below or near solidus during that process. The lithological and chemical heterogeneity of San Carlos mantle is thus compatible with a single-stage evolution, which is also supported by the striking consistency between Fe-Mg exchange and REE thermometric estimates (1057 and 1074 °C on average, respectively), indicating that harzburgites and lherzolites probably followed a similar P-T path and relatively little sub-solidus re-equilibration. These interpretations suggest that the development of melt extraction pathways promoted by reactive channeling instability is able to produce complex lithological heterogeneities during hydrous flux melting. This process provides a self-consistent explanation for the systematic enrichment of harzburgites observed in many mantle terranes and xenoliths worldwide. We argue that San Carlos is one of such examples where a ca 1.5-Ga continental lithosphere experienced localized flux melting and deformation during the tectonic reactivation of a Proterozoic subduction zone, providing new constraints on the mantle sources of volcanic activity in the Jemez Lineament

Role of Neuroinflammation and Blood-Brain Barrier Permutability on Migraine

Currently, migraine is treated mainly by targeting calcitonin gene-related peptides, although the efficacy of this method is limited and new treatment strategies are desired. Neuroinflammation has been implicated in the pathogenesis of migraine. In patients with migraine, peripheral levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α, are known to be increased. Additionally, animal models of headache have demonstrated that immunological responses associated with cytokines are involved in the pathogenesis of migraine. Furthermore, these inflammatory mediators might alter the function of tight junctions in brain vascular endothelial cells in animal models, but not in human patients. Based on clinical findings showing elevated IL-1β, and experimental findings involving IL-1β and both the peripheral trigeminal ganglion and central trigeminal vascular pathways, regulation of the Il-1β/IL-1 receptor type 1 axis might lead to new treatments for migraine. However, the integrity of the blood-brain barrier is not expected to be affected during attacks in patients with migraine

TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling

The mammalian target of rapamycin (mTOR) pathway is commonly activated in human cancers. The activity of mTOR complex 1 (mTORC1) signaling is supported by the intracellular positioning of cellular compartments and vesicle trafficking, regulated by Rab GTPases. Here we showed that tuftelin 1 (TUFT1) was involved in the activation of mTORC1 through modulating the Rab GTPase-regulated process. TUFT1 promoted tumor growth and metastasis. Consistently, the expression of TUFT1 correlated with poor prognosis in lung, breast and gastric cancers. Mechanistically, TUFT1 physically interacted with RABGAP1, thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promoted mTORC1 signaling. In addition, expression of TUFT1 predicted sensitivity to perifosine, an alkylphospholipid that alters the composition of lipid rafts. Perifosine treatment altered the positioning and trafficking of cellular compartments to inhibit mTORC1. Our observations indicate that TUFT1 is a key regulator of the mTORC1 pathway and suggest that it is a promising therapeutic target or a biomarker for tumor progression