The rapamycin.FKBP12 complex inhibits target of rapamycin (TOR) kinase in TORC1. We screened the yeast nonessential gene deletion collection to identify mutants that conferred rapamycin resistance, and we identified PMR1, encoding the Golgi Ca2+/Mn2+ -ATPase. Deleting PMR1 in two genetic backgrounds confers rapamycin resistance. Epistasis analyses show that Pmr1 functions upstream from Npr1 and Gln-3 in opposition to Lst8, a regulator of TOR. Npr1 kinase is largely cytoplasmic, and a portion localizes to the Golgi where amino acid permeases are modified and sorted. Nuclear translocation of Gln-3 and Gln-3 reporter activity in pmr1 cells are impaired, but expression of functional Gap1 in the plasma membrane of a pmr1 strain in response to nitrogen limitation is enhanced. These two phenotypes suggest up-regulation of Npr1 function in the absence of Pmr1. Together, our results establish that Pmr1-dependent Ca2+ and/or Mn2+ ion homeostasis is necessary for TOR signaling.
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http://dx.doi.org/10.1073/pnas.0604303103 | DOI Listing |
J Clin Med
December 2024
Pharmacy Department, Institut Català Oncologia (ICO), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet Llobregat, 08908 Barcelona, Spain.
Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), is actually used to prevent organ transplant rejection and treat metastatic breast, renal, and neuroendocrine cancers. Despite significant pharmacokinetic variability among patients, routine therapeutic drug monitoring (TDM) is not commonly used in oncology. The aim of this multicenter, prospective observational cohort study is to assess the prevalence of everolimus minimum concentration at a steady state (Cminss) falling outside the therapeutic range (10-26.
View Article and Find Full Text PDFCancers (Basel)
December 2024
Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London SW3 6JZ, UK.
There has been noteworthy progress in molecular characterisation and therapeutics in soft tissue sarcomas. Novel agents have gained regulatory approval by the FDA. Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma.
View Article and Find Full Text PDFAnimals (Basel)
January 2025
College of Fisheries, Guangdong Ocean University, Zhanjiang 524088, China.
A 10-week feeding study was conducted to examine the effects of dietary tryptophan (Trp) levels on the growth performance and protein metabolism of hybrid grouper (♀ × ♂) with the aim of determining the optimal Trp requirement. Six isonitrogenous and isolipidic experimental diets were formulated, containing varying levels of Trp (0.26%, 0.
View Article and Find Full Text PDFPoult Sci
December 2024
Department of Poultry Science, University of Georgia, Athens, GA, USA. Electronic address:
Valine and isoleucine are not only two of the indispensable amino acids (AAs) in chickens but also have special mechanisms with leucine within the branched-chain AA (BCAA) category. Therefore, we aimed to investigate how valine or isoleucine deficiency could specifically affect growth performance in broilers through various analyses. A total of 252 seven-day (d)-old male Cobb 500 broilers were allotted to three treatments with six replicates and reared until d 21.
View Article and Find Full Text PDFHum Cell
January 2025
Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi, 783-8505, Japan.
We previously examined the antitumor effects of short interfering RNA nanoparticles targeting mammalian target of rapamycin (mTOR) in an orthotopic pancreatic cancer mouse model. We herein report the inhibitory effects of the mTOR inhibitor rapamycin on tumor growth in a novel established mouse model of pancreatic cancer using human pancreatic cancer cell line-derived organoids. Gemcitabine, 5-fluorouracil, and gemcitabine plus nab-paclitaxel are clinically used to treat advanced pancreatic cancer.
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