The transcription factor ST18 regulates proapoptotic and proinflammatory gene expression in fibroblasts

Abstract

Suppression of tumorigenicity 18 (ST18) and the homologues neural zinc-finger protein-3 (NZF3) and myelin transcription factor 3 (Myt3) are transcription factors with unknown function. Previous studies have established that they repress transcription of a synthetic reporter construct consisting of the consensus sequence AAAGTTT linked to the thymidine kinase promoter. In addition, ST18 exhibits significantly reduced expression in breast cancer and breast cancer cell lines. We report here for the first time evidence that ST18 mediates tumor necrosis factor (TNF) -alpha induced mRNA levels of proapoptotic and proinflammatory genes in fibroblasts by mRNA profiling and silencing with ST18 small interfering RNA (siRNA). Gene set enrichment analysis and mRNA profiling support this conclusion by identifying several apoptotic and inflammatory pathways that are down-regulated by ST18 siRNA. In addition, ST18 siRNA reduces TNF-induced fibroblast apoptosis and caspase-3/7 activity. Fibroblasts that overexpress ST18 by transient transfection exhibit significantly increased apoptosis and increased expression of TNF-alpha, interleukin (IL) -1alpha, and IL-6. In addition, cotransfection of ST18 and a TNF-alpha or IL-1alpha reporter construct demonstrates that ST18 overexpression in fibroblasts significantly enhanced promoter activity of these genes. Taken together, these studies demonstrate that the transcription factor ST18/NZF3 regulates the mRNA levels of proapoptotic and proinflammatory genes in revealing a previously unrecognized function.

A Critical Role for the Neural Zinc Factor ST18 in Pancreatic β-Cell Apoptosis

“…However, the authors did not specifically measure apoptosis in their system. Another publication demonstrated a proinflammatory role for ST18 in fibroblasts (6). In this study, siRNA-mediated knockdown of ST18 reduced TNF␣-induced apoptosis and proinflammatory gene expression, whereas its overexpression significantly enhanced apoptosis.…”

“…Also, ectopic expression of ST18 reduced the tumorigenicity of MCF-7 cells (5), thereby suggesting a role for ST18 in tumor suppression. Furthermore, manipulation of ST18 expression in fibroblasts unraveled its potential proapoptotic and proinflammatory roles (6). ST18 expression was reported in the developing pancreas but its potential role in mature ␤-cells has never been investigated (4).…”

Deriving at candidate genes of metabolic stress from pancreas of WNIN/GR-Ob mutant rats

“…24 The mutants demonstrated an upregulation of 18 transcription factors (Table 1D) as compared with controls. These transcription factors have been reported to participate in apoptosis, proliferation, differentiation and stress responses, [25][26][27][28][29] which is in line with studies reported by Garnett et al 24 where they showed an upregulation of 41 transcription factors, in pre diabetic ZDF islets, in comparison with Zucker-Fatty islets. 24 Accelerated aging has been an yet another well documented phenomenon in these mutants with their average life span shortened to 1.5 y as compared with 2.5-3 y seen in Controls and Leans.…”

“…25 Supporting findings have shown that by silencing the activity of Tsc22d1, results in proliferation of hematopoetic precursors 26 while ST18 mediates tumor necrosis factor (TNFα) induced apoptosis and proinflammation in fibroblasts. 27 The role of RAX as an activator of PKR, has a diverse role in apoptosis induced stress is well reported. 28 An upregulation in the expression of CCAAT/enhancer binding proteins (CEBPA,CEBPE) by a fold of 2.73, 2.41 fold, have been linked to obesity in humans 29 and HMGA1 upregulated by 1.66 fold, is a key regulator of Insulin receptor gene expression, has been well associated with T2D in Chinese individuals.…”

A Structural Analysis of DNA Binding by Myelin Transcription Factor 1 Double Zinc Fingers

“…NZF3 has been shown to be a breast cancer tumor suppressor gene (8) and has also been implicated in the regulation of mRNA levels of proapoptotic and proinflammatory genes in fibroblasts (9). The other paralog, MyT1L, has recently attracted substantial interest due to its ability to act in concert with two other transcription factors (Ascl1 and Brnd2) to transform mouse as well as human stem cells directly into functional neurons (10 -12).…”