Journal
BLOOD
Volume 105, Issue 2, Pages 635-637Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2004-07-2681
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Funding
- NCI NIH HHS [F32CA84677] Funding Source: Medline
- NHLBI NIH HHS [R01HL63169] Funding Source: Medline
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Embryonic stem (ES) cells homozygous for a Shp-2 mutation (Shp-2(Delta46-110)) 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-2(Delta46-110) 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-2(Delta46-110) ES cells. Induction of 2 significantly up-regulated genes, suppressor of cytokine signaling-3 (SOCS-3) and Kruppel-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 verity the negative role of SOCS-3 on LIF signaling and provide a novel role for Klf4 in ES cell function.
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