STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells

Abstract

Signal transducers and activators of transcription (STATs) play key roles in growth factor-mediated intracellular signal transduction. In the present study using a constitutively active STAT5 mutant, we show that STAT5 has pleiotropic functions regulating cell proliferation, differentiation and apoptosis in an IL-3-dependent Ba/F3 cell line. The mutant STAT5 possessed constitutive tyrosine phosphorylation and DNA binding activity, induced expression of bcl-xL and pim-1 in the absence of IL-3 in Ba/F3 cells, and rendered Ba/F3 cells factor-independent. Unexpectedly, IL-3 treatment of the factor-independent Ba/F3 cells expressing the constitutively active STAT5 resulted in apoptosis within 24 h, or differentiation followed by cell death. In these cells, mRNA expression of growth inhibitory genes downstream of STAT5 such as CIS, JAB/SOCS-1/ SSI-1, and p21 WAF1/Cip1 was highly induced, correlating with prolonged hyper-phosphorylation of the mutant STAT5 after IL-3 stimulation. Of the STAT5-regulated genes, we found that constitutive expression of JAB/ SOCS-1/SSI-1 was sufficient to induce apoptosis of Ba/ F3 cells, while p21 WAF1/Cip1 could induce differentiation of these cells. In contrast, constitutive expression of pim-1 was sufficient to induce IL-3-independent growth of Ba/F3 cells. These findings suggest that a single transcription factor regulates cell fate by varying the intensity and duration of the expression of a set of target genes.

Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis

“…However, IL-3 treatment of the factorindependent cell line resulted in apoptosis within 24 h, or differentiation followed by cell death. This apoptosis might have been due to the concomitant upregulation of JAB/SOCS-1/SSI-1 and p21 by the super-active STAT5 signaling (Nosaka et al, 1999). Thus, differences in the fate of cells might be determined by the activation intensity and duration of specific STATs and may be cell-type specific.…”

Synergistic antitumor effect by coexpression of chemokine CCL21/SLC and costimulatory molecule LIGHT

“…Mouse LIGHT cDNA cloned in pcDNA3.1 was prepared as described previously. 18 Bicistronic expression vector of mouse CCL21 and LIGHT cDNAs cloned in pcDNA3.1 was prepared using the internal ribosome entry site (IRES) sequence in a bicistronic retroviral vector pMX-IRES/EGFP (kindly provided by Dr T Kitamura, University of Tokyo, Tokyo, Japan), 24 by standard PCR methods. C26 cells were then transfected with these expression vectors or the empty pcDNA3.1 vector by using Fugene 6 (Roche Molecular Biochemicals, Indianapolis, IN) and selected with Geneticin (G418).…”

The role of STATs in myeloid differentiation and leukemia

“…This regulation is speci®c for STAT3 and, for example, the c-myc promoter is not regulated by STAT5. A recent study has employed a constitutively active STAT5a mutant in the IL-3 dependent BaF3 cell line to analyse the regulation of proliferation and apoptosis (Nosaka et al, 1999). This mutant STAT5a was constitutively tyrosine phosphorylated and induced expression of Bcl-xL, pim-1, and c-myc in the absence of IL-3.…”