Tristetraprolin expression by keratinocytes protects against skin carcinogenesis.

Cancer is caused primarily by genomic alterations resulting in deregulation of gene regulatory circuits in key growth, apoptosis, or DNA repair pathways. Multiple genes associated with the initiation and development of tumors are also regulated at the level of mRNA decay, through the recruitment of RNA-binding proteins to AU-rich elements (AREs) located in their 3'-untranslated regions. One of these ARE-binding proteins, tristetraprolin (TTP; encoded by Zfp36), is consistently dysregulated in many human malignancies. Herein, using regulated overexpression or conditional ablation in the context of cutaneous chemical carcinogenesis, we show that TTP represents a critical regulator of skin tumorigenesis. We provide evidence that TTP controlled both tumor-associated inflammation and key oncogenic pathways in neoplastic epidermal cells. We identify Areg as a direct target of TTP in keratinocytes and show that EGFR signaling potentially contributed to exacerbated tumor formation. Finally, single-cell RNA-Seq analysis indicated that ZFP36 was downregulated in human malignant keratinocytes. We conclude that TTP expression by epidermal cells played a major role in the control of skin tumorigenesis.

The RNA-binding protein tristetraprolin regulates RALDH2 expression by intestinal dendritic cells and controls local Treg homeostasis.

AU-rich element (ARE)-mediated mRNA decay represents a key mechanism to avoid excessive production of inflammatory cytokines. Tristetraprolin (TTP, encoded by Zfp36) is a major ARE-binding protein, since Zfp36-/- mice develop a complex multiorgan inflammatory syndrome that shares many features with spondyloarthritis. The role of TTP in intestinal homeostasis is not known. Herein, we show that Zfp36-/- mice do not develop any histological signs of gut pathology. However, they display a clear increase in intestinal inflammatory markers and discrete alterations in microbiota composition. Importantly, oral antibiotic treatment reduced both local and systemic joint and skin inflammation. We further show that absence of overt intestinal pathology is associated with local expansion of regulatory T cells. We demonstrate that this is related to increased vitamin A metabolism by gut dendritic cells, and identify RALDH2 as a direct target of TTP. In conclusion, these data bring insights into the interplay between microbiota-dependent gut and systemic inflammation during immune-mediated disorders, such as spondyloarthritis.

A generic "micro-Stoney" method for the measurement of internal stress and elastic modulus of ultrathin films.

Accurate measurement of the mechanical properties of ultra-thin films with thicknesses typically below 100 nm is a challenging issue with an interest in many fields involving coating technologies, microelectronics, and MEMS. A bilayer curvature based method is developed for the simultaneous determination of the elastic mismatch strain and Young's modulus of ultra-thin films. The idea is to deposit the film or coating on very thin cantilevers in order to amplify the curvature compared to a traditional "Stoney" wafer curvature test, hence the terminology "micro-Stoney." The data reduction is based on the comparison of the curvatures obtained for different supporting layer thicknesses. The elastic mismatch strain and Young's modulus are obtained from curvature measurements of cantilevers before and after the film deposition. The data reduction scheme relies on both analytical and finite element calculations, depending on the magnitude of the curvature. The experimental validation has been performed on ultra-thin low pressure chemical vapor deposited silicon nitride films with thickness ranging between 54 and 133 nm deposited on silicon cantilevers. The technique is sensitive to the cantilever geometry, in particular, to the thickness ratio and width/thickness ratio. Therefore, the precision in the determination of the latter quantities determines the accuracy on the extracted elastic mismatch strain and elastic modulus. The method can be potentially applied to films as thin as a few nanometers.