Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4

• Published in: Blood 2005-01, Vol.105 (2), p.635-637
• Main Authors: Li, Yanjun, McClintick, Jeanette, Zhong, Li, Edenberg, Howard J., Yoder, Mervin C., Chan, Rebecca J.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell cycle, cell proliferation; Cell Differentiation - physiology; Cell physiology; DNA-Binding Proteins - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; Kruppel-Like Transcription Factors; Molecular and cellular biology; Muridae; Oligonucleotide Array Sequence Analysis; Repressor Proteins - genetics; Signal Transduction - physiology; Stem Cells - cytology; Stem Cells - physiology; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transcription Factors - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-07-2681

Embryonic stem (ES) cells homozygous for a Shp-2 mutation (Shp-2Δ46-110) demonstrate leukemia inhibitory factor (LIF) hypersensitivity and increased LIF-stimulated phosphorylation of signal transducer and activator of transcription (STAT3). We hypothesized that LIF-responsive genes in Shp-2Δ46-110 cells would represent potential candidates for molecules vital for ES cell self-renewal. Using microarray analysis, we detected 41 genes whose expression was modified by LIF in Shp-2Δ46-110 ES cells. Induction of 2 significantly up-regulated genes, suppressor of cytokine signaling–3 (SOCS-3) and Krüppel-like factor 4 (Klf4), was verified using Northern blotting. ES cells overexpressing SOCS-3 had an increased capacity to differentiate to hematopoietic progenitors, rather than to self-renew. In contrast, ES cells overexpressing Klf4 had a greater capacity to self-renew based on secondary embryoid body (EB) formation. Klf4-transduced d6 EBs expressed higher levels of Oct-4, consistent with the notion that Klf4 promotes ES cell self-renewal. These findings verify the negative role of SOCS-3 on LIF signaling and provide a novel role for Klf4 in ES cell function.