Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells

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Abstract
STAT5 is a member of a family of transcription factors that participate in the signal transduction pathways of many hormones and cytokines. Although STAT5 is suggested to play a crucial role in the biological effects of cytokines, its downstream target(s) associated with cell growth control is largely unknown. In a human interleukin‐3 (IL‐3)‐dependent cell line F‐36P‐mpl, the induced expression of dominant‐negative (dn)‐STAT5 and of dn‐ras led to inhibition of IL‐3‐dependent cell growth, accompanying the reduced expression of cyclin D1 mRNA. Also, both constitutively active forms of STAT5A (1*6‐STAT5A) and ras (H‐rasG12V) enabled F‐36P‐mpl cells to proliferate without added growth factors. In NIH 3T3 cells, 1*6‐STAT5A and H‐rasG12V individually and cooperatively transactivated the cyclin D1 promoter in luciferase assays. Both dn‐STAT5 and dn‐ras suppressed IL‐3‐induced cyclin D1 promoter activities in F‐36P‐mpl cells. Using a series of mutant cyclin D1 promoters, 1*6‐STAT5A was found to transactivate the cyclin D1 promoter through the potential STAT‐binding sequence at −481 bp. In electrophoretic mobility shift assays, STAT5 bound to the element in response to IL‐3. Furthermore, the inhibitory effect of dn‐STAT5 on IL‐3‐dependent growth was restored by expression of cyclin D1. Thus STAT5, in addition to ras signaling, appears to mediate transcriptional regulation of cyclin D1, thereby contributing to cytokine‐dependent growth of hematopoietic cells.