Tyrosine-phosphorylated Stat1 and Stat2 plus a 48-kDa protein all contact DNA in forming interferon-stimulated-gene factor 3.

Abstract

Interferon a induction of transcription operates through interferon-stimulated-gene factor 3 (ISGF), a transcription factor two components ofwhich are members of the newly characterized Stat family of transcription factors.Interferon a induces tyrosine phosphorylation of Statl and Stat2 proteins that associate and, together with a 48-kDa protein, form ISGF3. Evidence is presented that a heterodimer of Statl and Stat2 is present in ISGF3 and that Statl and the 48-kDa protein make precise contact, while Stat2 makes general contact, with the interferon-stimulated response element, the binding site of the ISGF3.Cytokine attachment to cell surface receptors triggers gene activation in the cell nucleus (1). Many of these extracellular polypeptides cause their intracellular changes through the Jak-Stat pathway (2). The Jak proteins are protein-tyrosine kinases associated with cell surface receptors that are activated by receptor occupation. The Stat proteins serve the dual function of signal transduction and activation of transcription. The first polypeptide ligand recognized to use this pathway was interferon a (IFN-a), which leads to activation of a nuclear DNA-binding complex called interferon-stimulated-gene factor 3 (ISGF3) (3, 4), which upon purification proved to contain four protein species, 113, 91, 84, and 48 kDa in size (5). The first three of these were the proteins that yielded sequence information establishing the sequence similarity in the Stat family (6, 7); it was also demonstrated that the 113-, 91-, and 84-kDa proteins (renamed Stat2, Statla, and Statlf3, respectively) were activated by phosphorylation on a single similarly located tyrosine (8-10). (The 91-and 84-kDa proteins differ only in a 38-aa carboxyl-terminal extension in the 91-kDa protein.) The 48-kDa protein,

IL-2 and long-term T cell activation induce physical and functional interaction between STAT5 and ETS transcription factors in human T cells

“…In that respect, some Stat proteins bind to other transcription factors or coactivators to activate transcription (Bhattacharya et al, 1996;Look et al, 1995;Muhlethaler-Mottet et al, 1998;Qureshi et al, 1995;Schaefer et al, 1995;Shen and Stavnezer, 1998;Zhang et al, 1996). More speci®cally, MGF/Stat5a has only been reported to form a complex with the glucocorticoid receptor (GR) on the b-casein promoter devoid of GR binding site (GRE) (Cella et al, 1998;StoÈ cklin et al, 1996).…”

Coordinated and Distinct Roles for IFN-αβ, IL-12, and IL-15 Regulation of NK Cell Responses to Viral Infection

“…Available biochemical data suggest potential overlapping spectra of transcription factors. IFN-␣␤ and IL-12 both can activate STAT1 (5)(6)(7)(8)(9). STAT4 is activated by IL-12 functions in both humans and mice (5)(6)(7)(8), and by IFN-␣␤ in humans (5,10,11).…”

A Preferential Role for STAT5, not Constitutively Active STAT3, in Promoting Survival of a Human Lymphoid Tumor

“…Heterodimer formation upon cytokine stimuli between different STAT family members, such as STAT1 and STAT3, STAT1 and STAT2, and STAT5a and STAT5b, has been shown earlier (45)(46)(47). In YT cells, we failed to identify any other STAT competent to dimerize with STAT3 via coimmunoprecipitation reactions, suggesting that STAT3 only forms homodimers within these cells (Fig.…”

“…Depending on the cytokine stimulus and cell type, activated STATs are able to form homo-and/or heterodimers that can contribute to their signal specificity (45)(46)(47). This model suggests that constitutively active STAT3 may dimerize with other STATs in the absence of cytokine.…”