caa a22 4500 606176233 CHVBK 20210128100746.0 cr unu---uuuuu 210128e20151201xx s 000 0 eng 10.1007/s00018-015-1976-1 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1976-1 Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells [Elektronische Daten] [Qingyu Zeng, Hai Zhang, Jiamin Qin, Zhigang Xu, Lin Gui, Beibei Liu, Chunxiao Liu, Chong Xu, Wen Liu, Shuangquan Zhang, Shile Huang, Long Chen] B-cell activating factor (BAFF) is involved in not only physiology of normal B cells, but also pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Rapamycin, a lipophilic macrolide antibiotic, has recently shown to be effective in the treatment of human lupus erythematosus. However, how rapamycin inhibits BAFF-stimulated B-cell proliferation and survival has not been fully elucidated. Here, we show that rapamycin inhibited human soluble BAFF (hsBAFF)-induced cell proliferation and survival in normal and B-lymphoid (Raji and Daudi) cells by activation of PP2A and inactivation of Erk1/2. Pretreatment with PD98059, down-regulation of Erk1/2, expression of dominant negative MKK1, or overexpression of wild-type PP2A potentiated rapamycin's suppression of hsBAFF-activated Erk1/2 and B-cell proliferation/viability, whereas expression of constitutively active MKK1, inhibition of PP2A by okadaic acid, or expression of dominant negative PP2A attenuated the inhibitory effects of rapamycin. Furthermore, expression of a rapamycin-resistant and kinase-active mTOR (mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR-T (mTOR-TE), conferred resistance to rapamycin's effects on PP2A, Erk1/2 and B-cell proliferation/viability, implying mTOR-dependent mechanism involved. The findings indicate that rapamycin inhibits BAFF-stimulated cell proliferation/survival by targeting mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells. Our data highlight that rapamycin may be exploited for preventing excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases. Springer Basel, 2015 Rapamycin nationallicence BAFF nationallicence mTOR nationallicence PP2A nationallicence Erk1/2 nationallicence B cells nationallicence 4E-BP1 : Eukaryotic initiation factor 4E binding protein 1 nationallicence Akt : Protein kinase B (PKB) nationallicence BAFF : B-cell activating factor of the TNF family nationallicence BLyS : B lymphocyte stimulator nationallicence BCMA : B-cell maturation antigen nationallicence CDK : Cyclin-dependent kinase nationallicence Erk1/2 : Extracellular signal-related kinases 1/2 nationallicence MAPK : Mitogen-activated protein kinase nationallicence MKK : Mitogen-activated protein kinase kinase nationallicence mTOR : Mammalian target of rapamycin nationallicence PP2A : Protein phosphatases 2A nationallicence S6K1 : Ribosomal protein S6 kinase 1 nationallicence SLE : Systemic lupus erythematosus nationallicence TACI : Transmembrane activator and cyclophilin ligand interactor nationallicence TALL-1 : TNF and apoptosis ligand-related leukocyte-expressed ligand1 nationallicence THANK : TNF homologue that activates apoptosis, nuclear factor κB, and c-Jun NH2-terminal kinase nationallicence Zeng Qingyu Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Zhang Hai Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Qin Jiamin Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Xu Zhigang Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Gui Lin Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Liu Beibei Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Liu Chunxiao Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Xu Chong Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Liu Wen Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Zhang Shuangquan Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Huang Shile Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, 71130-3932, Shreveport, LA, USA aut Chen Long Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut Cellular and Molecular Life Sciences Springer International Publishing 72/24(2015-12-01), 4867-4884 1420-682X 72:24<4867 2015 72 18 https://doi.org/10.1007/s00018-015-1976-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1976-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zeng Qingyu Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Zhang Hai Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Qin Jiamin Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Xu Zhigang Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Gui Lin Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Liu Beibei Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Liu Chunxiao Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Xu Chong Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Liu Wen Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Zhang Shuangquan Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 700 1- Huang Shile Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, 71130-3932, Shreveport, LA, USA aut NATIONALLICENCE 700 1- Chen Long Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, 210023, Nanjing, Jiangsu, People's Republic of China aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer International Publishing 72/24(2015-12-01), 4867-4884 1420-682X 72:24<4867 2015 72 18