Of alphas and betas: distinct and overlapping functions of STAT3 isoforms

Abstract

STAT3 is a pleiotropic factor activated by many different signals including cytokines, growth factors and oncogenes. It is involved in a striking number of functions and can activate distinct repertoires of genes in different contexts. Like other STAT factors, STAT3 exists in two isoforms generated by alternative splicing, the full length STAT3alpha and the truncated STAT3beta, generally thought to act as a dominant negative factor. However, STAT3beta is not transcriptionally inactive and is able to both activate and repress genes depending on cellular environment. These unique properties of the STAT3beta isoform may contribute to the extraordinary functional complexity of STAT3 physiological and pathological actions, revealed by conditional mutagenesis studies and not yet fully understood. With this in mind, we try here to summarize what is known about the structure and function of the alpha and beta STAT3 isoforms, both in vitro and in vivo. In addition, we report unpublished data describing the phenotype of mice where the STAT3alpha isoform was specifically ablated.

Antitumorigenic potential of STAT3 alternative splicing modulation

“…2D) must be mediated by either the repression of genes that promote oncogenesis/survival or by the activation of genes that inhibit growth/promote cell death. Microarray analysis revealed a specific expression signature associated with the acute switch from α to β that differs from that identified in other contexts (14,17,18). Validated genes that are specifically repressed by the induction of STAT3β include LEDGF, PCAF, IL8, CyclinC, PEX1, and STAT1β.…”

“…STAT3β can be efficiently phosphorylated at the key tyrosine 705 (Y705) but lacks serine 727 (S727), whose phosphorylation stimulates transcriptional activity (2). STAT3β can still bind to DNA as a homo-or heterodimer (with STAT3α or other transcription factors) (14). It was initially described as a dominant-negative factor and shown to inhibit gene transactivation, presumably by competitive promoter occupancy (15).…”

“…However, distinctive additional STAT3β properties have recently been described (6,14) indicating that STAT3β is not simply a truncated version of STAT3α with dominant-negative properties but a protein whose unique biological functions contribute to the complex biology of STAT3. In particular, expression of STAT3β (without STAT3α) rescues embryonic lethality in STAT3-null mice (17).…”

Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

“…It controls plasma B-cell differentiation, and it influences also T helper cell cytokine production through Stat3-dependent signaling (1,(25)(26)(27). Stat3 isoforms are known to cooperate with c-Jun or JunD proteins specifically (33). In addition, Stat3 response elements are often found close to AP-1 response elements and the c-fos oncogene or the junB tumor suppressor protein were identified as transcriptional targets of activated Stat3 (2-3).…”

STATus and Context within the Mammalian Nervous System

“…It has since been found to subserve diverse roles through evolution, and is implicated ubiquitously in several mammalian physiological systems, and in some pathological events. The mechanisms of Stat3 activation and its implications in mammalian development, its functions in complex physiological systems including the immune and nervous systems, and its role in pathological states including cancer are covered in several reviews, a few of which are referenced here (4)(5)(6)(7)(8).…”