Expression profiling of genes regulated by TGF-beta: Differential regulation in normal and tumour cells

Ranganathan, Prathibha; Agrawal, Alpna; Bhushan, Raghu; Chavalmane, Aravinda K.; Kalathur, Ravi Kiran Reddy; Takahashi, Takashi; Kondaiah, Paturu

doi:10.1186/1471-2164-8-98

Cited by 109 publications

(103 citation statements)

References 54 publications

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“…Expression of LMP1 with and without treatment with TGF-b1 in HPL1D cells mirrored that of LMP1 expression in A549 cells, although the response was less robust. This is consistent with the published report of comparative TGF-b1 responsiveness in the HPL1D cell line (34). To validate both the expression levels and function of LMP1 in the context of the EBV virus, A549 cells were infected with the BX-1 strain of EBV and exposed to TGF-b1.…”

Section: Discussionsupporting

confidence: 75%

The Epstein-Barr Virus Latent Membrane Protein 1 and Transforming Growth Factor–β1 Synergistically Induce Epithelial–Mesenchymal Transition in Lung Epithelial Cells

Sides¹,

Klingsberg²,

Shan³

et al. 2011

Am J Respir Cell Mol Biol

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Idiopathic Pulmonary Fibrosis (IPF) is characterized by thickening of the interstitium due to collagen deposition resulting in destruction of the alveolar architecture. A growing body of evidence suggests lung myofibroblasts are derived from epithelial origin through Epithelial‐Mesenchymal Transition (EMT). TGF‐b induces EMT in lung epithelial cells in a time and dose dependent manner. Higher occurrence of Epstein‐Barr virus (EBV) has been reported in lung tissue of IPF patients compared with that of non‐IPF patients. Our data show a remarkable increase in mesenchymal cell markers with concurrent reduction in the expression of epithelial cell markers in lung epithelial cells co‐treated with LMP‐1 and very low doses of TGF ƒÒ. We show that the pro‐EMT LMP1 signaling is primarily through the NF‐kB pathway and the pro‐EMT TGFb signaling is through the ERK pathway. LMP1 reduces TGFb signaling through Smad2/3 and increases TGFb ERK signaling. Together, these data suggest that the presence of EBV‐LMP1 in lung epithelial cells sensitizes these cells to TGF ƒÒ, synergistically inducing EMT. Our in vitro data may help explain the observation that IPF patients demonstrating positive staining for LMP‐1 in alveolar epithelial cells have a more rapid demise than patients in whom LMP‐1 is not detected.

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Section: Discussionsupporting

confidence: 75%

The Epstein-Barr Virus Latent Membrane Protein 1 and Transforming Growth Factor–β1 Synergistically Induce Epithelial–Mesenchymal Transition in Lung Epithelial Cells

Sides¹,

Klingsberg²,

Shan³

et al. 2011

Am J Respir Cell Mol Biol

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“…The implication of expression changes in the TGF-h pathway regulatory genes DAB2 and SKIL in FTEb samples during the luteal phase is highlighted by the observation that 15% of the significantly altered probe sets found by both SAM analyses (185 of 1,201 unique probe sets) correspond to genes known to be downstream TGF-h targets (47 -50), consistent with an altered TGF-h response (see Supplementary Tables S1 and S2). Such genes include DAB2 (47,49) and SKIL (48,49) themselves, in addition to well-established TGF-h targets ID2, ETS2, and PIM1 (50).…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

Tone

Begley²,

Sharma

et al. 2008

Clinical Cancer Research

125

111

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Purpose:To identify molecular alterations potentially involved in predisposition to adnexal serous carcinoma (SerCa) in the nonmalignant fallopian tube epithelium (FTE) of BRCA1/2 mutation carriers, given recent evidence implicating the distal FTE as a common source for SerCa. Experimental Design: We obtained and compared gene expression profiles of laser capture microdissected nonmalignant distal FTE from 12 known BRCA1/2 mutation carriers (FTEb) and 12 control women (FTEn) during the luteal and follicular phase, as well as 13 high-grade tubal and ovarian SerCa. Results: Gene expression profiles of tubal and ovarian SerCa specimens were indistinguishable by unsupervised cluster analysis and significance analysis of microarrays. FTEb samples as a group, and four individual FTEb samples from the luteal phase in particular, clustered closely with SerCa rather than normal control FTE. Differentially expressed genes from these four samples relative to other FTEb samples, as well as differentially expressed genes in all FTEb luteal samples relative to follicular samples, were mapped to the I2D protein-protein interaction database, revealing a complex network affecting signaling pathways previously implicated in tumorigenesis. Two candidates, disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) and Ski-like (SKIL), were further validated by real-time reverse transcription^PCR and tissue arrays. FTEb luteal and SerCa samples expressed higher levels of oncogenic SKIL and decreased levels of tumor suppressor DAB2, relative to FTEb follicular samples. Conclusions: These findings support a common molecular pathway for adnexal SerCa and implicate factors associated with the luteal phase in predisposition to ovarian cancer in BRCA mutation carriers.

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“…KLF5 is a nuclear protein, whereas Smad2 and Smad4 translocate into the nucleus upon TGF␤ signaling activation (3,4). However, the interaction between KLF5 and Smad4 was not affected by TGF␤ (Fig.…”

Section: Protein Interactions Between Klf5 and Other P15 Regulatorymentioning

confidence: 99%

Acetylation of KLF5 Alters the Assembly of p15 Transcription Factors in Transforming Growth Factor-β-mediated Induction in Epithelial Cells

Guo

Zhao

Dong

et al. 2009

Journal of Biological Chemistry

124

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KLF5 plays important roles in a variety of cellular processes including proliferation and differentiation. Recently KLF5 was shown to reverse its function in proliferative and p15 regulation upon transforming growth factor-␤ (TGF␤)-mediated acetylation. To understand how KLF5 acetylation functions in TGF␤-induced p15 transcription, we characterized the interactions of KLF5 with other transcription factors and promoter DNA elements in the context of TGF␤. KLF5 interacted with Smad2-4 and Miz-1 in a TGF␤-independent manner, but interacted with Myc only when TGF␤ was activated, and at least some of the interactions had an additive effect on TGF␤-induced p15 transcription. Oligo pulldown assays showed that binding of Myc to the Inr element was KLF5-dependent, and TGF␤ could enhance the binding when more KLF5 was available. Furthermore, TGF␤ induced an interaction between KLF5 and the p300 acetylase, and acetylation of KLF5 was necessary for Smad4 to associate with p300. Failure in KLF5 acetylation not only prevented p300-assembled Smad4-KLF5 complex formation on p15 promoter but also affected the binding of Smad4 and FOXO3 on the p15 promoter in vivo. These findings suggest that without TGF␤, some KLF5 associates with Smads in the nucleus and other KLF5 associates with Miz-1 on the p15 promoter to repress its transcription. Activation of TGF␤ recruits p300 to the KLF5-Smad complex to acetylate KLF5, and the complex with acetylated KLF5 binds to the Smad binding element and alters the binding of other factors to p15 promoter to induce its transcription. Transforming growth factor-␤ (TGF␤)2 is the most potent and widespread growth-inhibitory cytokine known in mammals (1, 2). TGF␤ signaling involves receptor binding, Smad modification and nuclear translocation, and the formation of Smad transcriptional complexes on gene promoters, regulating the expression of a large number of genes in different biological processes (3, 4). The same TGF␤ signaling has different regulatory roles in different contexts (1, 2, 5, 6), most likely through different transcriptional cofactors preexisting in different types of cells including proliferating epithelial cells that differentiate upon TGF␤ activation.The cyclin-dependent kinase inhibitor p15 (also named CDKN2B and p15INK4b ) is a well documented tumor suppressor in many types of cancers (7,8). The cytostatic effect of p15 is based on its inhibition of cyclin-dependent kinases CDK4 and CDK6, which arrests the cell cycle in the G 1 phase. p15 is an important effector of TGF␤ and is dramatically induced upon TGF␤ treatment in normal epithelial cells (9). Transcriptional induction of p15 by TGF␤ involves the formation of a Smad transcriptional complex containing Miz-1 (10), Myc (11), Sp1 (12) and FOXO (5). On the other hand, acetylase p300 is a well established co-activator of the TGF␤ pathway (13,14). In epithelial cells, TGF␤ signaling also recruits acetylase p300 to the Smad complex to acetylate some transcription factors and mediate TGF␤-induced transcription (6, 15).Human Kruppel-l...

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Expression profiling of genes regulated by TGF-beta: Differential regulation in normal and tumour cells

Cited by 109 publications

References 54 publications

The Epstein-Barr Virus Latent Membrane Protein 1 and Transforming Growth Factor–β1 Synergistically Induce Epithelial–Mesenchymal Transition in Lung Epithelial Cells

The Epstein-Barr Virus Latent Membrane Protein 1 and Transforming Growth Factor–β1 Synergistically Induce Epithelial–Mesenchymal Transition in Lung Epithelial Cells

Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

Acetylation of KLF5 Alters the Assembly of p15 Transcription Factors in Transforming Growth Factor-β-mediated Induction in Epithelial Cells

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