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

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.

EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

“…Stat5 proteins have been implicated in stimulation of cell growth, inhibition of apoptosis, and oncogenic development in certain other cells (Bowman et al, 2000). Among the targets of Stat5a and Stat5b are the genes of cyclin D1, p21 waf1/cip1 , c-Fos, and c-Myc (Quelle et al, 1996;Matsumura et al, 1997Matsumura et al, , 1999. At the time of seeding, most of the hepatocytes are in the early G 1 phase of the cell cycle (Christoffersen et al, 2000).…”

“…In contrast, Stat3 may have promitogenic and antiapoptotic effects and has been implicated in malignant transformation in some cells (Bromberg et al, 1999;Song and Rubin Grandis, 2000). Stat5a and Stat5b in hematopoietic cells seem to promote growth, inhibit apoptosis, and may be involved in malignant transformation (Matsumura et al, 1999;Nosaka et al, 1999;Demoulin et al, 2000), and are also essential mediators of the effects of prolactin (PRL) and growth hormone (GH) as well as IL-2 and other cytokines (Groner and Gouilleux, 1995;Grimley et al, 1999;Moriggl et al, 1999;Herrington et al, 2000;Lin and Leonard, 2000). However, although STAT proteins in some cells have been found to be phosphorylated and activated in response to growth factors, including EGF (Ruff-Jamison et al, 1993Richer et al, 1998;Guren et al, 1999;Luetteke et al, 1999;Olayioye et al, 1999), PDGF (Valgeirsdottir et al, 1998;Sachsenmaier et al, 1999), and VEGF (Bartoli et al, 2000), their exact function in receptor tyrosine kinase signaling has not been defined, and the role of STAT proteins in EGF receptor-mediated mitogenic mechanisms is not known.…”

Upregulation of rat Ccnd1 gene by exendin-4 in pancreatic beta cell line INS-1: interaction of early growth response-1 with cis-regulatory element

“…Ccnd1 expression appears to be predominantly regulated at the transcriptional level, although post-transcriptional mechanisms are also involved [13,14]. The promoter region of Ccnd1 contains multiple potential cis-regulatory elements, including binding sites for AP1, signal transducer and activator transcription 5 (STAT5), EGR1, specific protein 1 (SP1) and activating transcription factor (ATF)/cyclic AMP-responsive element binding protein (CREB), which are important for the transcriptional activation of Ccnd1 [15][16][17]. The AP1 binding site has been shown to be involved in angiotensin II-induced activation of the Ccnd1 promoter in human adrenal cells [15].…”

“…The AP1 binding site has been shown to be involved in angiotensin II-induced activation of the Ccnd1 promoter in human adrenal cells [15]. The STAT5 binding site has been implicated in cytokine-dependent proliferation of haematopoietic cells [16]. Oestrogen-induced activation of Ccnd1 was shown to be mediated by the ATF/CREB binding site, in which ATF2 and c-Jun formed heterodimers [17].…”

Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

“…Simultaneous inactivation of STAT5A and STAT5B genes results in a total defect in peripheric T cell proliferation due to a block in cell cycle progression (Moriggl et al, 1999). In hematopoietic cell lines, the use of dominant negative or constitutively active STAT5 mutants showed that this factor is required for cell growth (Mui et al, 1996;Onishi et al, 1998b;Matsumura et al, 1999). Similarly, hematopoietic cell lines expressing cytokine receptor mutants that are unable to activate STAT5, have a reduced proliferation rate (Gobert et al, 1996;Friedmann et al, 1996).…”