Showing papers by "Jochen Hess published in 2010"

Identification of the Rage-dependent gene regulatory network in a mouse model of skin inflammation

Abstract: In the past, molecular mechanisms that drive the initiation of an inflammatory response have been studied intensively. However, corresponding mechanisms that sustain the expression of inflammatory response genes and hence contribute to the establishment of chronic disorders remain poorly understood. Recently, we provided genetic evidence that signaling via the receptor for advanced glycation end products (Rage) drives the strength and maintenance of an inflammatory reaction. In order to decipher the mode of Rage function on gene transcription levels during inflammation, we applied global gene expression profiling on time-resolved samples of mouse back skin, which had been treated with the phorbol ester TPA, a potent inducer of skin inflammation. Ranking of TPA-regulated genes according to their time average mean and peak expression and superimposition of data sets from wild-type (wt) and Rage-deficient mice revealed that Rage signaling is not essential for initial changes in TPA-induced transcription, but absolutely required for sustained alterations in transcript levels. Next, we used a data set of differentially expressed genes between TPA-treated wt and Rage-deficient skin and performed computational analysis of their proximal promoter regions. We found a highly significant enrichment for several transcription factor binding sites (TFBS) leading to the prediction that corresponding transcription factors, such as Sp1, Tcfap2, E2f, Myc and Egr, are regulated by Rage signaling. Accordingly, we could confirm aberrant expression and regulation of members of the E2f protein family in epidermal keratinocytes of Rage-deficient mice. In summary, our data support the model that engagement of Rage converts a transient cellular stimulation into sustained cellular dysfunction and highlight a novel role of the Rb-E2f pathway in Rage-dependent inflammation during pathological conditions.

The Multi-Gene Family of Transcription Factor AP-1

Abstract: Publisher Summary This chapter focuses on the characteristic structural features of AP-1 subunits, mechanisms involved in modulation of AP-1 activity, and function of AP-1 proteins in cellular processes using mouse genetics. The DNA binding domain of AP-1 proteins, also known as the “bZip” region, can be divided in two evolutionary conserved, independently acting domains that include the basic domain, which is rich in basic amino acids and responsible for contacting the DNA and the leucine-zipper region characterized by heptad repeats of leucines forming a coiled-coil structure that is responsible for dimerization. Binding of AP-1 to DNA supports binding of several transcription factors to adjacent or overlapping binding sites (composite elements) to allow the formation of quaternary complexes. The interaction of NF-AT and Ets proteins with the IL-2 and collagenase promoters, respectively, may serve as paradigms for this type of protein–protein interaction. The transactivation domain (TAD) can be transferred to heterologous DNA binding domains, which do not require heterodimerization such as that of the yeast transcription factor GAL4. Such chimeric proteins permit identification of critical amino acids in TADs, and recognition that the TADs of individual Jun, Fos, and ATF proteins differ in their transactivation potential. The serum response element (SRE), which is bound by a ternary complex containing the transcription factor p67-SRF and p62-TCF, is required for the majority of extracellular stimuli including growth factors and phorbol esters. Changes in the phosphorylation pattern of SRF and, predominantly, TCF regulate Fos promoter activity by these stimuli. Other elements include the cAMP response element (CRE) and the Sis inducible enhancer (SIE) that is recognized by the STAT group of transcription factors.