Regulation of STAT protein synthesis by c-Cbl

Many cytokines and growth factors induce transcription of immediate early r esponse genes by activating members of the Signal Transducers and Activator s of Transcription (STAT) family. Although significant progress has been ma de in understanding the events that lead to the activation of STAT proteins , less, is known about the regulation of their expression. Here we report t hat murine embryonic fibroblasts derived from c-Cbl-deficient mice display significantly increased levels of STAT1 and STAT5 protein. In contrast, STA T2 and STAT3 expression, as well as the levels of the tyrosine kinases Jak1 and Tyk2, appear to be regulated independently of c-Cbl. Interestingly, th e half-life of STAT1 was, unaffected by the presence of c-Cbl, indicating t hat c-Cbl acts independently of STAT1 degradation. Further analysis reveale d similar levels of STAT1 mRNA, however, a dramatically increased rate of S TAT1 protein synthesis was observed in c-Cbl-deficient cells. Thus, our fin dings, demonstrate an additional control mechanism over STAT1 function, and also provide a novel biological effect of the Chl protein family.