A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells.

Abstract

Interleukin‐6 (IL‐6) induces either differentiation or growth of a variety of cells. Little is known about the molecular basis of this cellular decision. The family of signal transducer and activator of transcription (Stat) proteins are involved in signaling through a variety of cytokine and growth factor receptors, although their biological roles have not been established. To address whether Stat proteins play roles in IL‐6‐induced growth or differentiation, we introduced two types of mutant Stat3 acting in a dominant‐negative manner into M1 leukemic cells which respond to IL‐6 with growth arrest and terminal differentiation. We show that dominant‐negative forms of Stat3 inhibited both IL‐6‐induced growth arrest at G(0)/G1 and macrophage differentiation in the M1 transformants. Blocking of Stat activation resulted in inhibition of IL‐6‐induced repression of c‐myb and c‐myc. Furthermore, IL‐6 enhanced the growth of M1 cells primarily through shortening the length of the G1 period when Stat3 was suppressed. Thus IL‐6 generates both growth‐enhancing signals and growth arrest‐ and differentiation‐inducing signals at the same time. Stat3 may be a key molecule which determines the cellular decision from cell growth to differentiation in M1 cells.

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

“…We used two types of dominant-negative forms: STAT3F is mutated at Tyr705 residue, which is responsible for the formation of STAT3 dimmer; STAT3D is mutated at Glu434 and Glu435 residues, which are required for the DNAbinding activity (Nakajima et al, 1996). T24 cells were transfected with the HA-tagged expression vector of STAT3F or 3D, and G418-resistant colonies were isolated.…”

“…Wild-type HA-STAT3 and dominant-negative HA-STAT3F and HA-STAT3D constructs were described previously (Nakajima et al, 1996). Briefly, the tyrosine residue at 705 of STAT3 was replaced with phenylalanine to make STAT3F.…”

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

“…In M1 cells, at least, IFNg-responses which depend on Jak1 and Jak2 are not a ected by the overexpression of dominant negative STAT3 . Also in other cellular systems STAT3 is essential for the function of IL-6-type cytokines: for the survival of transfected BAF ± B03 pro-B-cells , for the di erentiation of promyelocytic M1 cells to macrophage-like cells (Minami et al, 1996;Nakajima et al, 1996;Yamanaka et al, 1996) and for the proliferation and maintenance of pluripotency of embryonic stem cells (Boeuf et al, 1997;Niwa et al, 1998). However, not all IL-6 e ects depend on STAT3: neurite outgrowth of PC12 pheochromocytoma cells needs signals via Y759 leading to activation of the tyrosine phosphatase SHP-2 and in turn to MAP kinase activation.…”

“…Myeloid M1 cells required functional STAT3 to di erentiate into macrophage-like cells (Minami et al, 1996;Nakajima et al, 1996). The inhibition of differentiation and maintenance of pluripotency of embryonic stem cells cultured in the presence of LIF similarly depended on STAT3 (Boeuf et al, 1997;Niwa et al, 1998).…”

Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

“…Recombinant human LIF was purchased from INTERGEN (Purchase, NY). Expression vectors, epitope-tagged STAT3, STAT3-LUC and STAT3-C were provided by Dr. T. Hirano (Osaka University, Osaka, Japan), Dr. J. F. Bromberg (Rockefeller Univ., New York, NY) and Dr. J. N. Ihle (St. Jude CRH, Memphis, TN), respectively [14,15]. Expression vectors for FLAG-EBNA2 and LMP1 were previously described [16,17].…”