Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

Stat proteins are latent transcription factors activated by tyrosine phosph orylation downstream of cytokine and growth factor receptors and have been implicated in a variety of cell growth regulatory pathways. Constitutive ph osphorylation has also been observed in various transformed cell line and i n primary malignant tissue, suggesting that Stat protein activation may con tribute to the transformed phenotype. One method to distinguish between a c ausative role in malignancy as opposed to bystander phosphorylation from th e increased tyrosine phosphorylation that accompanies transformation is to investigate cell growth and malignancy in the absence of particular Stat pr oteins using targeted gene disruptions in transgenic mice, Such studies sho w that Stat1 primarily mediates growth inhibitory signals and contributes t o the host rejection of tumors, and that its activation in transformed cell s is not necessary for malignancy. Activation of Stat5 can be both necessar y and sufficient for malignant transformation, and single Stat5-target gene s have been identified that are critical for heightened proliferation. None theless, some malignancies that are characterized by constitutively phospho rylated Stat5 are not altered by the loss of StatS protein. Its role in the se cases may be redundant with other transforming events that are in themse lves sufficient to cause disease, rendering tyrosine phosphorylation of Sta t5 unnecessary in these transformed cells.