Identification and Characterization of Constitutively Active Stat5
We have recently identified several constitutively active STAT5s using polymerase chain reaction (PCR)-driven random mutagenesis followed by retrovirus- mediated expression screening. One such mutant STAT5A1*6 harbors two point mutations; one in the effector domain and the other in the DNA binding domain, and induces factor-independent growth of several IL-3-dependent cell lines. The mutant STAT5A1*6 shows constitutive phosphorylation on its tyrosine residues, translocates into the nucleus, binds the target DNA sequence, and stimulates transcription in the absence of IL-3 stimulation. Further biochemical analyses suggested that a molecular basis for the constitutive activity of the mutant STAT5A is the increased stability of the phosphorylated form of STAT5. In addition to the ability of inducing factor- independent growth of IL-3-dependent cell lines, the mutant STAT5A induces apop- tosis or differentiation under some conditions or in a different cell line, implicating STAT5 as a molecular switch for pleiotropic functions of cytokine receptors. The relationship between active STAT5 and leukemogenesis will also be discussed.
KeywordsCodon Tyrosine Glycine Serine Polypeptide
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