The transcription factor SP1 regulates centriole function and chromosomal stability through a functional interaction with the mammalian target of rapamycin/raptor complex

Kim, Jiyoon; Kelly, Crystal; Olofsson, Beatrix A.; Torabi, Behzad; Sorokina, Elena M.; Azizkhan‐Clifford, Jane

doi:10.1002/gcc.20739

Cited by 30 publications

(30 citation statements)

References 89 publications

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“…The differential upregulation of genes under the control of these two anti-inflammatory transcriptional regulators provides a partial mechanism for the cardiac-specific effects of rapamycin, in the suppression of inflammatory cytokines we observed by both RNA-Seq and protein array data. Similar rapamycin-induced signaling mechanisms have also been identified in association with mTOR in other paradigms (Astrinidis et al , 2010; Ng et al. , 2011).…”

Section: Resultssupporting

confidence: 53%

Late-life rapamycin treatment reverses age-related heart dysfunction

et al. 2013

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Summary Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity-enhancing paradigm in mammalian tissues. We treated 24-month-old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late-life cardiovascular function with a reversal or attenuation of age-related changes in the heart. RNA-seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late-life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age-related inflammation.

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Section: Resultssupporting

confidence: 53%

Late-life rapamycin treatment reverses age-related heart dysfunction

et al. 2013

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“…Rapamycin has been shown to potentiate osteoblast differentiation via a p70s6K dependent manner [61]. It has also been proposed that mTOR signaling affects Sp1 transcriptional activity [62]. Sp1 has previously been implicated in TGFβ 1 signaling [63] and overexpression of Sp1 resulted in six-fold increase of basal Smad7 promoter activity [64], indirectly enhancing Smad7 activity, a TGFβ 1 inducible antagonist [65, 66].…”

Section: Discussionmentioning

confidence: 99%

A novel library screen identifies immunosuppressors that promote osteoblast differentiation

Darcy

Meltzer

Miller

et al. 2012

Bone

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Bone homeostasis can be compromised by an increase in osteoclast-mediated resorption and/or a decrease in osteoblast-mediated bone deposition. While many efforts have focused on treating osteoclast resorption, there has been less emphasis on identifying strategies for promoting osteoblast function. Herein, we describe a high-throughput screening assay to select for small molecules that augment bone morphogenetic protein-2 (BMP-2)-mediated osteoblast lineage commitment. After an initial screen of 5405 compounds; consisting of FDA-approved drugs, known bioactives, and compounds with novel chemical makeup, we identified 45 small molecules that promoted osteoblast commitment. Of the 45 candidates, there was a broad array of classes that included nine retinoid analogs/derivatives and four immunosuppressants, notably rapamycin and FK-506, which were chosen for further study. Treatment of osteoblast precursor cells with rapamycin or FK-506, either alone, or synergistically with BMP-2, increased levels of phospho-Smad1/5/8 protein and transcription of Runx-2, Osx and Smad-7, consistent with a role in promoting osteoblast differentiation. Only FK-506 was able to enhance osteocalcin transcripts and alizarin red staining, both late markers for differentiation. When osteoblast differentiation was suppressed with exogenous TGF-β1 treatment, rapamycin (but not FK-506) was able to rescue expression of differentiation markers, indicating distinct but overlapping activity of these compounds. Collectively, these data add to an understanding of pathways engaged in osteoblastogenesis, support a role for non-redundant immunosuppressant signaling, and provide a novel approach for the discovery of potentially therapeutic compounds that affect bone remodeling.

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“…Lamin was used as a loading control for nuclear extracts. Lamin was preferred to the transcription factor SP1, which is also frequently used as a marker for nuclear extracts, because it was recently reported to be also located in the cytoplasm []. Secondary goat antimouse antibody was purchased from Pierce, Rockford, USA.…”

Section: Methodsmentioning

confidence: 99%

Subcellular localization of FOXP3 in human regulatory and nonregulatory T cells

et al. 2012

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IntroductionNaturally occurring CD4 + CD25 + regulatory (Treg) T cells play a fundamental role in maintaining immune homeostasis [1]. Alterations in the number or functional activity of Treg cells have been observed in several immunological disease states [2]. Furthermore, studies in mice have reported beneficial effects of Treg-cell-based immunotherapies in a wide range of disease models. This has quickly prompted the initiation of early phase clinical Correspondence: Dr. Michael H. Albert e-mail: michael.albert@med.uni-muenchen.de trials in humans with promising preliminary results [3][4][5]. A stringent definition of the human Treg-cell phenotype is, however, a prerequisite for such studies. Therefore, much effort has been put into characterizing human Treg cells based on the expression of specific markers, ideally on the cell surface. In addition to CD25, other surface markers such as CD62L, GITR, LAG-3, and CTLA-4 were identified to be expressed in Treg cells, albeit not exclusively so [6][7][8][9][10]. These markers are also up-regulated in recently activated nonregulatory human T cells, limiting their usefulness as markers [11][12][13]. The same is true for CD127 which was found to be absent on Treg cells but not on conventional T cells. It has recently been shown to be down-regulated upon activation C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1628 Thomas Magg et al. Eur. J. Immunol. 2012. 42: 1627-1638. These findings cast some shadow on numerous studies using these surface markers to describe the Treg-cell phenotype in human disease [15][16][17]. The identification of one or more dependable identifier molecules could significantly propel Treg-cell research and clinical application forward. The transcription factor forkhead box protein P3 (FOXP3) is considered to be the master regulator for the development and function of Treg cells [18,19]. It is highly expressed in Treg cells and generally accepted as the single best marker to identify Treg cells [19]. But just as the surface markers named above, FOXP3 expression is not Treg cell-specific but is also up-regulated in nonregulatory CD4+ T cells upon activation [20]. Kinetic studies of FOXP3 expression in activated human T cells reveal a transient up-regulation of the protein that is not sufficient to induce a regulatory phenotype in vitro [11]. These findings might suggest a differential function of FOXP3 in activated T cells and in Treg cells. The complex nature of FOXP3 is further highlighted by the presence of different splice variants [20][21][22], whose functions remain largely obscure. One would expect that the cellular functions of FOXP3 are tightly controlled, FOXP3 being such an important molecule for immune homeostasis in general and Treg-cell function in particular. Recently, it has been reported that a substantial subset of murine naturally occurring Treg cells can lose their FOXP3 expression and become auto aggressive, stressing the notion that regulation of FOXP3 expression is an important physiological switch in ...

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The transcription factor SP1 regulates centriole function and chromosomal stability through a functional interaction with the mammalian target of rapamycin/raptor complex

Cited by 30 publications

References 89 publications

Late-life rapamycin treatment reverses age-related heart dysfunction

Late-life rapamycin treatment reverses age-related heart dysfunction

A novel library screen identifies immunosuppressors that promote osteoblast differentiation

Subcellular localization of FOXP3 in human regulatory and nonregulatory T cells

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