Chunming Liu

Regulation of beta-catenin stability is essential for Wnt signal transduction during development and tumorigenesis. It is well known that serine-phosphorylation of beta-catenin by the Axin-glycogen synthase kinase (GSK)-3beta complex targets beta-catenin for ubiquitination-degradation, and mutations at critical phosphoserine residues stabilize beta-catenin and cause human cancers. How beta-catenin phosphorylation results in its degradation is undefined. Here we show that phosphorylated beta-catenin is specifically recognized by beta-Trcp, an F-box/WD40-repeat protein that also associates with Skp1, an essential component of the ubiquitination apparatus. beta-catenin harboring mutations at the critical phosphoserine residues escapes recognition by beta-Trcp, thus providing a molecular explanation for why these mutations cause beta-catenin accumulation that leads to cancer. Inhibition of endogenous beta-Trcp function by a dominant negative mutant stabilizes beta-catenin, activates Wnt/beta-catenin signaling, and induces axis formation in Xenopus embryos. Therefore, beta-Trcp plays a central role in recruiting phosphorylated beta-catenin for degradation and in dorsoventral patterning of the Xenopus embryo.

Transcription factor Kruppel-like factor 4 (Klf4) is essential for somatic cell reprogramming. In addition, Klf4 seems to play a redundant role along with other Klf family proteins in embryonic stem (ES) cell self-renewal. However, how Klf4 regulates ES cell self-renewal and somatic cell reprogramming is still poorly understood. Here we report that Klf4 is required for both ES cell self-renewal and maintenance of pluripotency and that the expression of Klf4 prevents ES cell differentiation in response to withdrawal of leukemia inhibitory factor (LIF) or bone morphogenetic protein 4 (BMP4). In addition, Klf4 directly binds to the promoter region of Nanog and regulates its expression. Expression of Nanog prevents ES cell differentiation even when Klf4 gene expression is knocked down. On the other hand, knockdown of Nanog expression induces differentiation of ES cells that overexpress Klf4. Taken together, these results demonstrate that Klf4 functions upstream of Nanog in ES cell self-renewal and in preventing ES cell differentiation.