Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation.
Stat5a and Stat5b are discretely encoded transcription factors that mediate signals for a broad spectrum of cytokines. Their activation is often an integral component of redundant cytokine signal cascades involving complex cross-talk and pleiotropic gene regulation by Stat5 has been implicated in cellular functions of proliferation, differentiation and apoptosis with relevance to processes of hematopoiesis and immunoregulation, reproduction, and lipid metabolism. Although Stat5a and Stat5b show peptide sequence similarities of > 90%, targeted gene disruptions in mice yield distinctive phenotypes. Prolactin-directed mammary gland maturation fails without functional Stat5a, while disruption of Stat5b in males mitigates growth hormone effects on hepatic function and body mass. The molecular basis for this biologic dichotomy is probably multifaceted. Limited structural dissimilarities between the Stat5a and Stat5b transactivation domains, or subtle differences in the DNA-binding affinities of Stat5 dimer pairs undoubtedly influence gene regulation, but cell-dependent asymmetries in availability of phosphorylated Stat5 can be an underlying factor. Differences in serine phosphorylation(s) of Stat5a and Stat5b, or Stat5 associations with adaptor proteins or co-transcription factors are other potential sources of functional disparity and the signal amplitude, frequency or duration also can be significant. In addition to Stat5 signal attenuation by phosphatase actions or classical feedback inhibition, truncated forms of Stat5 lacking in transactivation capacity may compete upstream for activation and diminish access of full length molecules to DNA binding sites.
Grimley
P M
PM
Department of Pathology, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20854, USA.
Dong
F
F
Rui
H
H
D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008894:Milk Proteins; D008969:Molecular Sequence Data; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins
D016207:Cytokines; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D020033:Protein Isoforms; D018121:Receptors, Cytokine; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D012694:Serine