A novel approach for the generation of genetically modified mammary epithelial cell cultures yields new insights into TGFβ signaling in the mammary gland

Kohn, Ethan A.; Du, Zhifeng; Sato, Misako; Schyndle, Catherine M.H. Van; Welsh, Michael A.; Yu, Yong A.; Stuelten, Christina H.; Tang, Binwu; Ju, Wenjun; Böttinger, Erwin P.; Wakefield, Lalage M.

doi:10.1186/bcr2728

Cited by 23 publications

(25 citation statements)

References 41 publications

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“…Thus, the MAPK pathway interacts in important ways with the SMAD pathway. However, SMAD activation is an important component of the cytostatic response to TGF-β, as indicated by the effects of small molecule inhibition of the TβR-1 kinase (Seay et al 2005), SMAD3 knockout cells (Kohn et al 2010) and dominant-negative SMAD3 mutants (Liu et al 1997). …”

Section: Modulation Of Tgf-β Signals In the Vascular Environmentmentioning

confidence: 99%

Transforming growth factor-β and atherosclerosis: interwoven atherogenic and atheroprotective aspects

2011

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Age-related progression of cardiovascular disease is by far the largest health problem in the US and involves vascular damage, progressive vascular fibrosis and the accumulation of lipid-rich atherosclerotic lesions. Advanced lesions can restrict flow to key organs and can trigger occlusive thrombosis resulting in a stroke or myocardial infarction. Transforming growth factor-beta (TGF-β) is a major orchestrator of the fibroproliferative response to tissue damage. In the early stages of repair, TGF-β is released from platelets and activated from matrix reservoirs; it then stimulates the chemotaxis of repair cells, modulates immunity and inflammation and induces matrix production. At later stages, it negatively regulates fibrosis through its strong antiproliferative and apoptotic effects on fibrotic cells. In advanced lesions, TGF-β might be important in arterial calcification, commonly referred to as “hardening of the arteries”. Because TGF-β can signal through multiple pathways, namely the SMADs, a MAPK pathway and the Rho/ROCK pathways, selective defects in TGF-β signaling can disrupt otherwise coordinated pathways of tissue regeneration. TGF-β is known to control cell proliferation, cell migration, matrix synthesis, wound contraction, calcification and the immune response, all being major components of the atherosclerotic process. However, many of the effects of TGF-β are essential to normal tissue repair and thus, TGF-β is often thought to be “atheroprotective”. The present review attempts to parse systematically the known effects of TGF-β on both the major risk factors for atherosclerosis and to isolate the role of TGF-β in the many component pathways involved in atherogenesis.

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Section: Modulation Of Tgf-β Signals In the Vascular Environmentmentioning

confidence: 99%

Transforming growth factor-β and atherosclerosis: interwoven atherogenic and atheroprotective aspects

2011

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“…Such cell lines appear to retain many biological properties of the cells from which they were derived, including gene expression patterns and response to signalling pathways (Kohn et al, 2010). We derived two sets of cell lines from dissected E10.5 forelimb buds to represent the most posterior third of the distal limb (cell lines P1 and P2) or the anterior two-thirds (A1 and A2) (Fig.…”

Section: Image Analysismentioning

confidence: 99%

Anterior-posterior differences in HoxD chromatin topology in limb development

et al. 2012

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SUMMARYA late phase of HoxD activation is crucial for the patterning and growth of distal structures across the anterior-posterior (A-P) limb axis of mammals. Polycomb complexes and chromatin compaction have been shown to regulate Hox loci along the main body axis in embryonic development, but the extent to which they have a role in limb-specific HoxD expression, an evolutionary adaptation defined by the activity of distal enhancer elements that drive expression of 5Ј Hoxd genes, has yet to be fully elucidated. We reveal two levels of chromatin topology that differentiate distal limb A-P HoxD activity. Using both immortalised cell lines derived from posterior and anterior regions of distal E10.5 mouse limb buds, and analysis in E10.5 dissected limb buds themselves, we show that there is a loss of polycomb-catalysed H3K27me3 histone modification and a chromatin decompaction over HoxD in the distal posterior limb compared with anterior. Moreover, we show that the global control region (GCR) long-range enhancer spatially colocalises with the 5Ј HoxD genomic region specifically in the distal posterior limb. This is consistent with the formation of a chromatin loop between 5Ј HoxD and the GCR regulatory module at the time and place of distal limb bud development when the GCR participates in initiating Hoxd gene quantitative collinearity and Hoxd13 expression. This is the first example of A-P differences in chromatin compaction and chromatin looping in the development of the mammalian secondary body axis (limb).

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“…Furthermore, in vitro studies have shown that Smad2 and Smad3 have unique functions in mammary epithelium and oncogenesis, in which Smad3 and not Smad2 is critical to inducing TGFβ-mediated apoptosis, cell cycle arrest and EMT. 18,19 …”

Section: Tgfβ and Smad Signalingmentioning

confidence: 99%