Since its discovery in mice and humans 19 years ago, the contribution of alternatively spliced Stat3, Stat3β, to the overall functions of Stat3 has been controversial.
Tyrosine-phosphorylated (p) Stat3β homodimers are more stable, bind
DNA more avidly, are less susceptible to dephosphorylation, and exhibit distinct intracellular dynamics, most notably markedly prolonged nuclear retention, compared to pStat3α homodimers. Overexpression of one or the other
isoform in cell lines demonstrated that Stat3β acted as a dominant-negative of Stat3α in transformation assays; however, studies with mouse strains deficient in one or the other
isoform indicated distinct contributions of Stat3
isoforms to
inflammation. Current immunological
reagents cannot differentiate Stat3β
proteins derived from alternative splicing vs. proteolytic cleavage of Stat3α. We developed
monoclonal antibodies that recognize the 7 C-terminal
amino acids unique to Stat3β (CT7) and do not cross-react with Stat3α. Immunoblotting studies revealed that levels of Stat3β
protein, but not Stat3α, in
breast cancer cell lines positively correlated with overall pStat3 levels, suggesting that Stat3β may contribute to constitutive Stat3 activation in this
tumor system. The ability to unambiguously discriminate splice alternative Stat3β from proteolytic Stat3β and Stat3α will provide new insights into the contribution of Stat3β vs. Stat3α to
oncogenesis, as well as other
biological and
pathological processes.