Kieslinger M, Woldman I, Moriggl R, Hofmann J, Marine J C, Ihle J N, Beug H, Decker T
Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria.
Genes Dev. 2000 Jan 15;14(2):232-44.
Stat5 is activated by multiple receptors of hematopoietic cytokines. To study its role during hematopoiesis, we have generated primary chicken myeloblasts expressing different dominant-negative (dn) alleles of Stat5. This caused a striking inability to generate mature cells, due to massive apoptosis during differentiation. Bcl-2 was able to rescue differentiating cells expressing dnStat5 from apoptosis, suggesting that during cytokine-dependent differentiation the main function of the protein is to ensure cell survival. Our findings with dnStat5-expressing chicken myeloblasts were confirmed with primary hematopoietic cells from Stat5a/Stat5b-deficient mice. Bone marrow cells from these animals displayed a strong increase in apoptotic cell death during GM-CSF-dependent functional maturation in vitro. The antiapoptotic protein Bcl-x was induced by GM-CSF and IL-3 in a Stat5-dependent fashion. Ectopic expression of Bcl-x rescued Stat5-deficient bone marrow cells from apoptosis, indicating that Stat5 promotes the survival of myeloid progenitor cells through its ability to induce transcription of the bcl-x gene. Finally, the recruitment of myeloid cells to inflammatory sites was found strongly impeded in Stat5-deficient mice. Taken together, our findings suggest that Stat5 may promote cytokine-dependent survival and proliferation of differentiating myeloid progenitor cells in stress or pathological situations, such as inflammation.
Stat5可被多种造血细胞因子受体激活。为研究其在造血过程中的作用，我们构建了表达不同显性负性（dn）Stat5等位基因的原代鸡成髓细胞。这导致了显著的无法生成成熟细胞的现象，原因是分化过程中出现大量细胞凋亡。Bcl-2能够挽救表达dnStat5的分化细胞免于凋亡，这表明在细胞因子依赖的分化过程中，该蛋白的主要功能是确保细胞存活。我们对表达dnStat5的鸡成髓细胞的研究结果，在Stat5a/Stat5b基因敲除小鼠的原代造血细胞中得到了证实。这些动物的骨髓细胞在体外GM-CSF依赖的功能成熟过程中，凋亡细胞死亡显著增加。抗凋亡蛋白Bcl-x以Stat5依赖的方式被GM-CSF和IL-3诱导。Bcl-x的异位表达挽救了Stat5缺陷的骨髓细胞免于凋亡，表明Stat5通过诱导bcl-x基因转录的能力促进髓系祖细胞的存活。最后，发现Stat5缺陷小鼠中髓系细胞向炎症部位的募集受到严重阻碍。综上所述，我们的研究结果表明，在应激或病理情况下，如炎症，Stat5可能促进分化中的髓系祖细胞的细胞因子依赖的存活和增殖。
