STAT3β, a Splice Variant of Transcription Factor STAT3, Is a Dominant Negative Regulator of Transcription

Abstract

The 89-kDa STAT3 protein is a latent transcription factor which is activated in response to cytokines (interleukin (IL)-5 and -6) and growth factors (epidermal growth factor). Binding of IL-5 to its specific receptor activates JAK2 which leads to the tyrosine phosphorylation of STAT3 proteins. Here we report the cloning of a cDNA encoding a variant of the transcription factor STAT3 (named STAT3beta) which was isolated by screening an eosinophil cDNA library. Compared to wild-type STAT3, STAT3beta lacks an internal domain of 50 base pairs located near the C terminus. This splice product is a naturally occurring isoform of STAT3 and encodes a 80-kDa protein. We found by reconstitution of the human IL-5R in COS cells that like STAT3, STAT3beta is phosphorylated on tyrosine and binds to the pIRE from the ICAM-1 promoter after IL-5 stimulation. However, STAT3beta fails to activate a pIRE containing promoter in transient transfection assays. Instead, co-expression of STAT3beta inhibits the transactivation potential of STAT3. These results suggests that STAT3beta functions as a negative regulator of transcription.

The role of STATs in myeloid differentiation and leukemia

“…Three distinct isoforms of STAT3 have been described, that all arise from a single gene (Figure 2). STAT3b, an alternatively spliced form of STAT3a (full length STAT3), lacks the c-terminal 55 amino acids (Schaefer et al, 1995;Caldenhoven et al, 1996). In addition, a 72 kDa STAT3g protein was described that is also truncated at its c-terminus and is derived from STAT3a by limited proteolysis (Chakraborty and Tweardy, 1998a).…”

IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line

“…In addition, isoforms of STAT1, STAT3, STAT5A, STAT5B that lack the COOH terminus, a region highly variable among STAT members containing the transactivation domain, have been described. These isoforms arise through an alternative splicing mechanism or a speci®c protein processing and are thought to be natural dominant negative forms of STAT proteins (Schindler et al, 1992;Azam et al, 1995Azam et al, , 1997Caldenhoven et al, 1996;Kazansky et al, 1995;Meyer et al, 1998;Schaefer et al, 1997;Wang et al, 1996).…”

Molecular characterization and IFN signal pathway analysis of Carassius auratus CaSTAT1 identified from the cultured cells in response to virus infection

“…In mammals, naturally occurring STAT variants have been detected for several STATs, including STAT1 [7,8], STAT3 [5,6], and STAT5 [3,4]. These variants all exhibit truncations in their C-terminal domains, in which the conserved PMSP sequence is missing [12].…”

“…These variants all exhibit truncations in their C-terminal domains, in which the conserved PMSP sequence is missing [12]. For example, compared to STAT3a, STAT3b lacks an internal domain of 50 bp located near the C terminus but this deletion causes a shift in the open reading frame resulting in the formation of a stop codon after 7 aa [5], and STAT1b lacks the 38 Cterminal amino acid residues of STAT1a [7,8].…”