| 1. |
- Brodin, Greger, et al.
(författare)
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Efficient TGF-β Induction of the Smad7 Gene Requires Cooperation between AP-1, Sp1, and Smad Proteins on the Mouse Smad7 Promoter
- 2000
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 275:37, s. 29023-29030
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Tidskriftsartikel (refereegranskat)abstract
- Sma- and Mad-related protein 7 (Smad7) is an antagonist of transforming growth factor-beta (TGF-beta) signaling, which has been shown to be induced by TGF-beta itself and also by other stimuli. In an effort to understand the molecular mechanisms underlying the transcriptional regulation of the Smad7 gene by TGF-beta, we cloned and functionally characterized a mouse genomic DNA fragment encompassing the mouse Smad7 proximal promoter. This region was found to contain a CpG island and to be devoid of a classical TATA box. Cloned upstream of a promoter-lacking luciferase reporter gene, this region conferred robust TGF-beta-induced transcription. Point mutations in a palindromic Smad binding element, abolished TGF-beta inducibility completely. Through the use of electrophoretic mobility shift assays, we showed the presence of Smad2, Smad3, and Smad4 in complexes binding to the Smad binding element. Interestingly, we also found that point mutation and/or deletion of binding sites for the transcription factors activator protein-1 and Sp1 led to an attenuation of the basal promoter activity, as well as of the TGF-beta-mediated induction of Smad7. Taken together, our data imply that Smads, together with activator protein-1 and Sp1 transcription factors, are essential for efficient Smad7 promoter activity.
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| 2. |
- Brodin, Gert, 1963-, et al.
(författare)
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Plasma dynamics at the Schwinger limit and beyond
- 2023
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Ingår i: Physical review. E. - : American Physical Society. - 2470-0045 .- 2470-0053. ; 107:3
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Tidskriftsartikel (refereegranskat)abstract
- Strong field physics close to or above the Schwinger limit are typically studied with vacuum as initial condition or by considering test particle dynamics. However, with a plasma present initially, quantum relativistic mechanisms such as Schwinger pair creation are complemented by classical plasma nonlinearities. In this work we use the Dirac-Heisenberg-Wigner formalism to study the interplay between classical and quantum mechanical mechanisms in the regime of ultrastrong electric fields. In particular, the effects of initial density and temperature on the plasma oscillation dynamics are determined. Finally, comparisons with competing mechanisms such as radiation reaction and Breit-Wheeler pair production are made.
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| 3. |
- Brodin, Greger, 1968-
(författare)
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Smad7 in TGF-β Signalling
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Members of the transforming growth factor-β (TGF-β) superfamily of growth and differentiation factors regulate a vast array of biological functions in the adult, and are of great importance in governing cell fate determination and patterning in the developing embryo. The TGF-β signal is propagated intracellularly by Smad proteins resulting in transcriptional responses. Smad6 and Smad7 are inhibitory Smads known to downregulate the TGF-β signal and thereby possibly modulating the biological response. This thesis describes a functional analysis of the inhibitory Smad7 from an in vitro and in vivo perspective.The prostate gland is dependent on androgens for its growth and differentiation. Androgen withdrawal can cause regression and apoptosis in normal and malignant prostate. Previous studies suggest a role for TGF-β in the apoptotic mechanism. We investigated the expression levels of Smad proteins in the rat ventral prostate as well as in an androgen sensitive prostate tumor model (Dunning R3327 PAP) by immunohistochemistry. We observed an increased immunoreactivity for Smad3, Smad4 and phosphorylated Smad2 in the rat ventral prostate epithelial cells after castration, as well as in the prostate tumor cells. Expression of inhibitory Smad6 and Smad7 were also increased in both normal and malignant prostate in response to castration. Several studies have shown that Smad7 is upregulated in response to TGF-β stimuli, suggesting a role in a negative feedback loop attenuating the TGF-β response. We investigated the molecular mechanism behind that response by studying the transcriptional regulation of the Smad7 gene. We identified a palindromic Smad binding element (SBE) in the promoter. Point mutations introduced into the SBE abolished transcriptional activation via TGF-β. We also observed that mutating or deleting binding motifs for Sp1 and AP-1, led to an attenuation of the TGF-β mediated transcriptional induction as well as the basal promoter activity.Gene ablation of Smad proteins has revealed specific physiological and developmental roles. We analysed mice targeted on the Smad7 locus. The mice appeared viable and fertile with a slight reduction in litter size, suggesting a perinatal loss. Biochemical analysis of mouse embryonic fibroblasts (MEFs) showed no major difference between wild type and mutant MEFs.
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| 4. |
- Li, Ronggui, et al.
(författare)
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Deletion of exon I of SMAD7 in mice results in altered B cell responses
- 2006
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Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 176:11, s. 6777-6784
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Tidskriftsartikel (refereegranskat)abstract
- The members of the TGF-beta superfamily, i.e., TGF-beta isoforms, activins, and bone morphogenetic proteins, regulate growth, differentiation, and apoptosis, both during embryonic development and during postnatal life. Smad7 is induced by the TGF-beta superfamily members and negatively modulates their signaling, thus acting in a negative, autocrine feedback manner. In addition, Smad7 is induced by other stimuli. Thus, it can fine-tune and integrate TGF-beta signaling with other signaling pathways. To investigate the functional role(s) of Smad7 in vivo, we generated mice deficient in exon I of Smad7, leading to a partial loss of Smad7 function. Mutant animals are viable, but significantly smaller on the outbred CD-1 mouse strain background. Mutant B cells showed an overactive TGF-beta signaling measured as increase of phosphorylated Smad2-positive B cells compared with B cells from wild-type mice. In agreement with this expected increase in TGF-beta signaling, several changes in B cell responses were observed. Mutant B cells exhibited increased Ig class switch recombination to IgA, significantly enhanced spontaneous apoptosis in B cells, and a markedly reduced proliferative response to LPS stimulation. Interestingly, LPS treatment reverted the apoptotic phenotype in the mutant cells. Taken together, the observed phenotype highlights a prominent role for Smad7 in development and in regulating the immune system's response to TGF-beta.
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