Research Report 2010 - MDC

Figure 2. Mutual requirements for Eda-A1/Edar/NF-κB and Wnt/β-catenin in early hair follicle development. (A) Wnt activity is maintained in theabsence of Eda-A1/Edar/NF-κB activity. Wnt reporter mice (cond-lacZ) were mated with mice deficient in Eda-A1 (cond-lacZ;Ta/Ta) or Edar expression(cond-lacZ;dl/dl), or with mice lacking NF-κB activity (cond-lacZ;∆N). X-Gal stained E14.5 embryos are depicted. Arrows point to Wnt activity inplacodes and other ectodermal appendages, such as whiskers and eyelids. Note that the placode pattern in embryos lacking epidermal Eda-A1/Edar/NF-κB activity is irregular when compared to controls. Thus, placode pattern refinement requires NF-κB activity. We and others haveshown that Wnt inhibitor Dkk4 is an NF-κB target gene. Dkk4 is known to be involved in placode patterning and spacing. (B) X-Gal stained condlacZ;dl/dland cond-lacZ;∆N embryos at E15.5, when hair placodes have already started to grow. Focal Wnt activity in hair placodes has disappearedin the absence of Eda-A1/Edar/NF-κB activity. We have found that Wnt10b is a direct target gene of Eda-A1/Edar/NF-κB, providing a possible explanationfor this observation. Panel (C) illustrates a model for the molecular interplay of Wnt/β-catenin and Edar/NF-κB signaling pathways. Notethat Wnt10a and Lef-1 have previously been described as potential NF-κB target genes.revealed that constitutive NF-κB drives the expressionof genes with important functions in cell cycle progression,programmed cell death and tropism or migrationof tumor cells. Thus, a central pathogenic role of theIKK/NF-κB pathways is very likely and the distinct contributionsof canonical and non-canonical pathways forthe biology of the tumor cells are now under investigation.In addition to IKK/NF-κB, Hodgkin lymphoma cellsreveal aberrant activation of transcription factor AP-1(activating protein 1), composed of the c-Jun and JunBsubunits. AP-1 cooperates with NF-κB to superactivate asubset of NF-κB target genes in HL. Furthermore, Stat5ais activated by NF-κB in HL cells and may synergize withNF-κB at the level of common target genes.By a genome-wide determination of genes regulated byIKK and NF-κB in activated B cell lineage cells, we couldshow that induced AP-1 activity is entirely dependenton IKK and NF-κB, which regulate expression of Jun, ATFand Maf members. This cross-talk is under further80 Cancer Research