Abstract:
:The immunosuppressant and anticancer drug rapamycin works by inducing inhibitory protein complexes with the kinase mTOR, an important regulator of growth and proliferation. The obligatory accessory partner of rapamycin is believed to be FK506-binding protein 12 (FKBP12). Here we show that rapamycin complexes of larger FKBP family members can tightly bind to mTOR and potently inhibit its kinase activity. Cocrystal structures with FKBP51 and FKBP52 reveal the modified molecular binding mode of these alternative ternary complexes in detail. In cellular model systems, FKBP12 can be functionally replaced by larger FKBPs. When the rapamycin dosage is limiting, mTOR inhibition of S6K phosphorylation can be enhanced by FKBP51 overexpression in mammalian cells, whereas FKBP12 is dispensable. FKBP51 could also enable the rapamycin-induced hyperphosphorylation of Akt, which depended on higher FKBP levels than rapamycin-induced inhibition of S6K phosphorylation. These insights provide a mechanistic rationale for preferential mTOR inhibition in specific cell or tissue types by engaging specific FKBP homologs.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
März AM,Fabian AK,Kozany C,Bracher A,Hausch Fdoi
10.1128/MCB.00678-12subject
Has Abstractpub_date
2013-04-01 00:00:00pages
1357-67issue
7eissn
0270-7306issn
1098-5549pii
MCB.00678-12journal_volume
33pub_type
杂志文章abstract::The generation of two daughter cells with the same genetic information requires error-free chromosome segregation during mitosis. Chromosome transmission fidelity is dependent on spindle structure/function, which requires Asp1 in the fission yeast Schizosaccharomyces pombe Asp1 belongs to the diphosphoinositol pentaki...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00047-18
更新日期:2018-04-16 00:00:00
abstract::It is well established that steroid receptor function requires interaction with coactivators. However, the mechanisms through which steroid receptors elicit precise assembly of coactivator complexes and the way the steroid activation signal is transduced remain elusive. Using a T47D cell line stably integrated with a ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.23.11.3763-3773.2003
更新日期:2003-06-01 00:00:00
abstract::To understand how DEXD/H-box proteins recognize and interact with their cellular substrates, we have been studying Prp28p, a DEXD/H-box splicing factor required for switching the U1 snRNP with the U6 snRNP at the precursor mRNA (pre-mRNA) 5' splice site. We previously demonstrated that the requirement for Prp28p can b...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00384-09
更新日期:2009-07-01 00:00:00
abstract::Nuclear receptor corepressors (N-CoR) and silencing mediator for retinoid and thyroid receptors (SMRT) have both been implicated in thyroid hormone receptor (TR)-mediated repression. Here we show that endogenous N-CoR, TBL1, and histone deacetylase 3 (HDAC3), but not HDAC1, -2, or -4, are recruited to a stably integra...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.23.15.5122-5131.2003
更新日期:2003-08-01 00:00:00
abstract::Using nuclear runoff transcription assays we demonstrated that alpha interferon-mediated induction of transcription of four mRNAs in HeLa monolayer cells needed ongoing protein synthesis and that such a need could be obviated by pretreating the cells with gamma interferon which, by itself, did not induce transcription...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.7.1.528
更新日期:1987-01-01 00:00:00
abstract::DNA supercoiling in the chloroplast of the unicellular green alga Chlamydomonas reinhardtii was found to change with a diurnal rhythm in cells growing in alternating 12-h dark-12-h light periods. Highest and lowest DNA superhelicities occurred at the beginning and towards the end of the 12-h light periods, respectivel...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.18.12.7235
更新日期:1998-12-01 00:00:00
abstract::Chronic inflammation plays important roles in cancer initiation and progression. Resolving chronic inflammation or blocking inflammatory signal transduction may prevent cancer development. Here, we report that the combined low-dose use of two anti-inflammatory drugs, aspirin and triptolide, reduces spontaneous lung ca...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00149-17
更新日期:2017-07-14 00:00:00
abstract::SCIP is a POU domain transcription factor expressed by glial progenitor cells in the peripheral and central nervous systems (dividing Schwann cells and O-2A cells, respectively), where it appears to act as a repressor of myelin-specific genes. We have isolated genomic clones encoding the rat SCIP gene. Comparison of t...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.11.9.4642
更新日期:1991-09-01 00:00:00
abstract::Heterokaryons of Saccharomyces cerevisiae have been constructed utilizing the kar1-1 mutation, which prevents nuclear fusion during conjugation (J. Conde and G. Fink, Proc. Natl. Acad. Sci. U.S.A. 73:3651-3655, 1976). Each heterokaryon contained two haploid nuclei that were marked on several chromosomes. They segregat...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.1.3.245
更新日期:1981-03-01 00:00:00
abstract::The DNA-binding hemopoietic zinc finger transcription factor GATA1 promotes terminal megakaryocyte differentiation and restrains abnormal immature megakaryocyte expansion. How GATA1 coordinates these fundamental processes is unclear. Previous studies of synthetic and naturally occurring mutant GATA1 molecules demonstr...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.25.19.8592-8606.2005
更新日期:2005-10-01 00:00:00
abstract::Expression of the reaper gene (rpr) correlates with the initiation of apoptosis in Drosophila melanogaster. Transient expression of rpr in the lepidopteran SF-21 cell line induced apoptosis displaying nuclear condensation and fragmentation, oligonucleosomal ladder formation, cell surface blebbing, and apoptotic body f...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.17.2.667
更新日期:1997-02-01 00:00:00
abstract::The transcription factor Mcm1 is regulated by adjacent binding of a variety of different factors regulating the expression of cell-type-specific, cell cycle-specific, and metabolic genes. In this work, we investigate a new class of Mcm1-regulated promoters that are cell cycle regulated and peak in late M-early G(1) ph...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.22.2.430-441.2002
更新日期:2002-01-01 00:00:00
abstract::The synthesis of 60S ribosomal subunits in Saccharomyces cerevisiae requires Tif6p, the yeast homologue of mammalian eukaryotic translation initiation factor 6 (eIF6). In the present work, we have isolated a protein kinase from rabbit reticulocyte lysates on the basis of its ability to phosphorylate recombinant human ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.23.17.6187-6199.2003
更新日期:2003-09-01 00:00:00
abstract::For proper male sexual differentiation, anti-Müllerian hormone (AMH) must be tightly regulated during embryonic development to promote regression of the Müllerian duct. However, the molecular mechanisms specifying the onset of AMH in male mammals are not yet clearly defined. A DNA-binding element for the steroidogenic...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.18.11.6653
更新日期:1998-11-01 00:00:00
abstract::Skp2B, an F-box protein of unknown function, is frequently overexpressed in breast cancer. In order to determine the function of Skp2B and whether it has a role in breast cancer, we performed a two-hybrid screen and established transgenic mice expressing Skp2B in the mammary glands. We found that Skp2B interacts with ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01239-07
更新日期:2007-11-01 00:00:00
abstract::Tie1 is an orphan receptor tyrosine kinase that is expressed almost exclusively in endothelial cells and that is required for normal embryonic vascular development. Genetic studies suggest that Tie1 promotes endothelial cell survival, but other studies have suggested that the Tie1 kinase has little to no activity, and...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.22.6.1704-1713.2002
更新日期:2002-03-01 00:00:00
abstract::The E2F transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor. We have previously shown that E2F3 plays a critical role in mediating the mitogen-induced activation of E2F-responsive genes and contributes to both the inappropriate proliferation and the p53-dependent apopt...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.23.18.6542-6552.2003
更新日期:2003-09-01 00:00:00
abstract::Transcription by RNA polymerase I (pol I), pol II, and pol III requires the TATA-binding protein (TBP). This protein functions in association with distinct TBP-associated factors (TAFs) which may specify the nature of the polymerase selected for initiation at a promoter site. In the pol III transcription system, the T...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.13.12.7953
更新日期:1993-12-01 00:00:00
abstract::Glucocorticoid production in the adrenal cortex is activated in response to an increase in cyclic AMP (cAMP) signaling. The nuclear protein p54(nrb)/NONO belongs to the Drosophila behavior/human splicing (DBHS) family and has been implicated in several nuclear processes, including transcription, splicing, and RNA expo...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00993-14
更新日期:2015-04-01 00:00:00
abstract::A 215-base-pair (bp) region of the mouse MOPC 41 kappa light-chain immunoglobulin gene enhancer has been analyzed for specific binding of lymphoid and nonlymphoid nuclear factors. Mobility shift assays with a series of overlapping DNA fragments have mapped DNA-binding sites for three unique factors. The B-cell-specifi...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.9.10.4239
更新日期:1989-10-01 00:00:00
abstract::Protein kinase activities were measured in Rous sarcoma virus-infected baby hamster kidney (BHK) cells that express v-src (BHK [v-src]) and compared with those of revertant and control BHK cells. We observed about a fivefold-higher tyrosine phosphorylating activity in BHK (v-src) cell extracts, which was due to src bu...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.4.5.973
更新日期:1984-05-01 00:00:00
abstract::Deltex1, Deltex2, and Deltex4 form a family of related proteins that are the mammalian homologues of Drosophila Deltex, a known regulator of Notch signals. Deltex1 is highly induced by Notch signaling in thymocytes, and overexpression of Deltex1 in T-cell progenitors can block Notch signals, suggesting that Deltex1 ma...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00149-06
更新日期:2006-10-01 00:00:00
abstract::Fragments of African green monkey (Cercopithecus aethiops) DNA (3.5 to 18.0 kilobases) were inserted downstream from the thymidine kinase (TK, tk) coding region in pTK206/SV010, a gene construct which lacks both copies of the hexanucleotide 5'-AATAAA-3' and contains a simian virus 40 origin of replication, allowing it...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.3.4.643
更新日期:1983-04-01 00:00:00
abstract::In the budding yeast Saccharomyces cerevisiae, Cdc37 is required for the productive formation of Cdc28-cyclin complexes. The cdc37-1 mutant arrests at Start with low levels of Cdc28 protein, which is predominantly unphosphorylated at Thr169, fails to bind cyclin, and has little protein kinase activity. We show here th...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.20.3.749-754.2000
更新日期:2000-02-01 00:00:00
abstract::Meltrin alpha (ADAM12) is a metalloprotease-disintegrin whose specific expression patterns during development suggest that it is involved in myogenesis and the development of other organs. To determine the roles Meltrin alpha plays in vivo, we generated Meltrin alpha-deficient mice by gene targeting. Although the numb...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.23.1.55-61.2003
更新日期:2003-01-01 00:00:00
abstract::GATA1 is a master regulator of erythropoiesis, expression of which is regulated by multiple discrete cis-acting elements. In this study, we examine the activity of a promoter-proximal double GATA (dbGATA) motif, using a Gata1 bacterial artificial chromosome (BAC)-transgenic green fluorescent protein (GFP) reporter (G1...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01011-14
更新日期:2015-03-01 00:00:00
abstract::SATB1 is expressed primarily in thymocytes and orchestrates temporal and spatial expression of a large number of genes in the T-cell lineage. SATB1 binds to the bases of chromatin loop domains in vivo, recognizing a special DNA context with strong base-unpairing propensity. The majority of thymocytes are eliminated by...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.21.16.5591-5604.2001
更新日期:2001-08-01 00:00:00
abstract::The selective expression of a unique copy gene in several mammalian tissues has been approached by studying the regulatory sequences needed to control expression of the rat phosphoenolpyruvate carboxykinase (PEPCK) gene in transgenic mice. A transgene containing the entire PEPCK gene, including 2.2 kb of the 5'-flanki...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.12.3.1396
更新日期:1992-03-01 00:00:00
abstract::Interleukin-6 (IL-6) and leukemia inhibitory factor (LIF), two multifunctional cytokines, recently have been identified as physiological inducers of hematopoietic cell differentiation which also induce terminal differentiation and growth arrest of the myeloblastic leukemic M1 cell line. In this work, it is shown that ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.11.5.2375
更新日期:1991-05-01 00:00:00
abstract::We find that during embryogenesis the expression of HMGN1, a nuclear protein that binds to nucleosomes and reduces the compaction of the chromatin fiber, is progressively down-regulated throughout the entire embryo, except in committed but continuously renewing cell types, such as the basal layer of the epithelium. In...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.26.2.592-604.2006
更新日期:2006-01-01 00:00:00