Convergence of Transforming Growth Factor-β and Vitamin D Signaling Pathways on SMAD Transcriptional Coactivators

Yanagisawa, Junn; Yanagi, Yasuo; Masuhiro, Yoshikazu; Suzawa, Miyuki; Watanabe, Michiko; Kashiwagi, Kouji; Toriyabe, Takeshi; Kawabata, Masahiro; Miyazono, Kohei; Kato, Shigeaki

doi:10.1126/science.283.5406.1317

Cited by 413 publications

(289 citation statements)

References 37 publications

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“…To this aim, we first examined the possibility that SRC-1 and Smad3 proteins may undergo direct protein Á protein interactions. In the mammalian two-hybrid, Gal4-based, transactivation assay, we demonstrated that VP16AD-SRC-1 does not enhance Gal4BD-Smad3-mediated transcription, neither in the absence nor in the presence of TGF-b (Figure 4a), suggesting that Smad3 does not directly interact with SRC-1, as previously evoked by Yanagisawa et al (1999). In contrast, the physical interaction between SRC-1 and p300, previously described in the literature (Glass and Rosenfeld, 2000), was confirmed in another mammalian two-hybrid assay, as expression of VP16AD-SRC-1 potently enhanced Gal4BD-p300-mediated transactivation (Figure 4b), reflecting direct SRC-1/p300 interaction.…”

Section: Src-1 Interacts With P300 Not With Smad3supporting

confidence: 49%

The steroid receptor co-activator-1 (SRC-1) potentiates TGF-β/Smad signaling: role of p300/CBP

et al. 2005

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The three related 160-kDa proteins, SRC-1, TIF-2 and RAC-3, were initially identified as factors interacting with nuclear receptors. They have also been reported to potentiate the activity of other transcription factors such as AP-1 or NF-jB. The aim of this work was to identify whether SRC-1 interferes with the TGF-b/Smad signaling pathway, and if so, to identify its underlying mechanisms of action. Using transient cell transfection experiments performed in human dermal fibroblasts with the Smad3/4-specific (SBE) 4 -lux reporter construct, as well as the human PAI-1 promoter, we determined that SRC-1 enhances TGF-b-induced, Smad-mediated, transcription. Likewise, SRC-1 overexpression potentiated TGF-binduced upregulation of PAI-1 steady-state mRNA levels. Using a mammalian two-hybrid system, we demonstrated that SRC-1 interacts with the transcriptional co-activators p300/CBP, but not with Smad3. Overexpression of the adenovirus E1A oncoprotein, an inhibitor of CBP/ p300 activity, prevented the enhancing effect of SRC-1 on Smad3/4-mediated transcription, indicating that p300/ CBP may be required for SRC-1 effect. Such hypothesis was validated, as expression of a mutant form of SRC-1 lacking the CBP/p300-binding site failed to upregulate Smad3/4-dependent transcription, while full-length SRC-1 potentiated p300 . Smad3 interactions. These results identify SRC-1 as a novel Smad3/4 transcriptional partner, facilitating the functional link between Smad3 and p300/CBP.

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Section: Src-1 Interacts With P300 Not With Smad3supporting

confidence: 49%

The steroid receptor co-activator-1 (SRC-1) potentiates TGF-β/Smad signaling: role of p300/CBP

et al. 2005

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“…Almost all transcription factors upregulated by MafB in CD34 þ cells have been demonstrated to play a role or to be somehow involved in the regulation of mono-macrophage differentiation. In particular: (1) Fos family members, 14 responsible for the assembly of the AP-1 transcription complex together with Jun proteins, and the c-Maf gene 9 have been reported to induce a partial macrophage maturation of several myeloid cell lines (M1, U937, HL60); (2) the PPARd nuclear receptor is a transactivator of the CCL2/MCP1 chemokine in macrophages; 30 (3) MiT family transcription factors are macrophage-restricted, even if very little is known about their target genes; 15 (4) SMAD3 is a transcription factor responsible for the TGFb pathway intracellular effects, 16 previously demonstrated to promote growth arrest and monocyte differentiation at least in cell line models (U937); 31 (5) NFIL3 32 drives the transcription of IL-3, a cytokine involved in the regulation of granulo-monocytopoiesis. 18 The upregulated expression of such transcription factors may consequently provide the molecular basis to explain the effects played by MafB in the control of mono-macrophage differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Among transcription factors upregulated by MafB transduction, we could detect genes belonging to the Maf (c-Maf), 8 AP-1 (FosL2), 14 PPAR (d member), 10 MiT (MitF), 15 SMAD (SMAD3), 16 and Hox (HLX1) 17 families, already described for their capacity to regulate monocyte differentiation/activation or other aspects of hematopoiesis ( Figure 7).…”

Section: Genetic Program Activated By Mafb Transduction In Cd34 þ Hemmentioning

confidence: 99%

Virally mediated MafB transduction induces the monocyte commitment of human CD34+ hematopoietic stem/progenitor cells

et al. 2006

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Upregulation of specific transcription factors is a generally accepted mechanism to explain the commitment of hematopoietic stem cells along precise maturation lineages. Based on this premise, transduction of primary hematopoietic stem/ progenitor cells with viral vectors containing the investigated transcription factors appears as a suitable experimental model to identify such regulators. Although MafB transcription factor is believed to play a role in the regulation of monocytic commitment, no demonstration is, to date, available supporting this function in normal human hematopoiesis. To address this issue, we retrovirally transduced cord blood CD34 þ hematopoietic progenitors with a MafB cDNA. Immunophenotypic and morphological analysis of transduced cells demonstrated the induction of a remarkable monomacrophage differentiation. Microarray analysis confirmed these findings and disclosed the upregulation of macrophage-related transcription factors belonging to the AP-1, MAF, PPAR and MiT families. Altogether our data allow to conclude that MafB is a key regulator of human monocytopoiesis.

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“…Similar to the interaction between 1,25(OH) 2 D-bound VDR and Smad3, OCT-bound VDR physically interacts with pSmad3 ( Figure 10c). 35 This interaction recruits PPM1A to pSmad3, and then inhibits pSmad3-dependent transcription of TGF-b1 by dephosphorylating pSmad3 (Figure 10c). All of our findings indicated that OCT blocked the autoinduction of TGF-b1 by recruiting the PPM1A/VDR complex to pSmad3.…”

Section: Discussionmentioning

confidence: 99%

Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3

Inoue

Matsui

Hamano

et al. 2012

Laboratory Investigation

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Tubulointerstitial fibrosis (TIF) is one of the major problems in nephrology because satisfactory therapeutic strategies have not been established. Here, we demonstrate that maxacalcitol (22-oxacalcitriol (OCT)), an analog of active vitamin D, protects the kidney from TIF by suppressing the autoinduction of transforming growth factor-b1 (TGF-b1). OCT suppressed the tubular injury index, interstitial volume index, collagen I positive area, and mRNA levels of extracellular matrix genes in unilateral ureteral-obstructed kidneys in rats. Although the renoprotective mechanism of active vitamin D in previous studies has been mainly attributed to the suppression of renin, OCT did not affect renal levels of renin or angiotensin II. We found that TGF-b1 itself induces its expression in a phospho-Smad3 (pSmad3)-dependent manner, and that OCT ameliorated TIF by abrogating this 'autoinduction'. Under the stimulation of TGF-b1, pSmad3 bound to the proximal promoter region of the TGF-b1 gene. Both OCT and SIS3, a Smad3 inhibitor, abrogated the binding of pSmad3 to the promoter and consequently attenuated the autoinduction. TGF-b1 increased both the nuclear levels of protein phosphatase Mg 2 þ /Mn 2 þ -dependent 1A (PPM1A), a pSmad3 phosphatase, and the interaction levels between the vitamin D receptor (VDR) and PPM1A. In the absence of OCT, however, the interaction between pSmad3 and PPM1A was weak; therefore, it was insufficient to dephosphorylate pSmad3. The PPM1A/VDR complex was recruited to pSmad3 in the presence of both TGF-b1 and OCT. This recruitment promoted the dephosphorylation of pSmad3 and attenuated the pSmad3-dependent production of TGF-b1. Our findings provide a novel approach to inhibit the TGF-b pathway in fibrotic diseases. Tubulointerstitial fibrosis (TIF) is the final common pathway for most forms of progressive kidney diseases. 1-3 Numerous studies revealed that two major signaling pathways, the renin-angiotensin system (RAS) and the transforming growth factor-b1 (TGF-b1)/Smad system, have important roles in the pathogenesis of TIF. [3][4][5][6] However, because satisfactory therapeutic strategies have not been established, TIF remains one of the major problems in nephrology.One of the candidates that protect the kidney from TIF is active vitamin D because it is a negative regulator of renin. 7,8 Several lines of studies revealed the renin-suppressive effect of 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. [9][10][11][12] In addition to 1,25(OH) 2 D, a less-calcemic analog, paricalcitol, has been revealed to suppress renin in the kidney. 13 These findings provide a rationale for active vitamin D therapy in renal diseases with high local renin.

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Convergence of Transforming Growth Factor-β and Vitamin D Signaling Pathways on SMAD Transcriptional Coactivators

Cited by 413 publications

References 37 publications

The steroid receptor co-activator-1 (SRC-1) potentiates TGF-β/Smad signaling: role of p300/CBP

The steroid receptor co-activator-1 (SRC-1) potentiates TGF-β/Smad signaling: role of p300/CBP

Virally mediated MafB transduction induces the monocyte commitment of human CD34+ hematopoietic stem/progenitor cells

Maxacalcitol ameliorates tubulointerstitial fibrosis in obstructed kidneys by recruiting PPM1A/VDR complex to pSmad3

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