A variety of cytokines mediate the activation of Janus protein tyrosine kinases (Jaks). The Jaks then phosphorylate cellular substrates, including members of the signal transducers and activators of transcription (Stat) family of transcription factors. Among the Stats, the two highly related proteins, Stat5a and Stat5b, are activated by a variety of cytokines. To assess the role of the Stat5 proteins, mutant mice were derived that have the genes deleted individually or together. The phenotypes of the mice demonstrate an essential, and often redundant, role for the two Stat5 proteins in a spectrum of physiological responses associated with growth hormone and prolactin. Conversely, the responses to a variety of cytokines that activate the Stat5 proteins, including erythropoietin, are largely unaffected.

relate to their functions (detailed below). Specifically, the Stats colocalize with Stat1-Stat4, Stat2-St. Jude Children's Research Hospital Stat6, and Stat3-Stat5a/Stat5b tightly linked on chromo-Department of Biochemistry somes 1, 10, and 11, respectively. This suggests that Memphis, Tennessee 38105 there existed an evolutionarily primordial gene that duplicated and that this duplication, or the original, was further duplicated. In recent evolution, the Stat5 gene Signal transducers and activators of transcription further duplicated. Since the Drosophila gene appears (STATs) were first identified as a unique family of DNAto be most related to Stat5, the Stat3-Stat5a/Stat5b site binding proteins approximately four years ago. Since may represent the ancestral gene site. that time, the number of mammalian family members STAT: Structure and Functional Domains has grown, and in this issue of Cell, two reports now The STATs share several conserved structural and funcextend the STAT family to Drosophila (Hou et al., 1996; tional domains (Figure 1). The most interesting and con-Yan et al., 1996). The STATs have drawn considerable served domain is a potential phosphotyrosine-binding, attention because of their unique mode of activation SRC homology 2 domain (SH2). Several observations and the diversity of biological effects they are thought support this prediction, including the finding that mutato mediate from antiviral responses to cell transformation of the predicted phosphotyrosine-binding Arg tion. As in any emerging field, there has been a rapid residue eliminates activity. However, the isolated SH2 explosion of information and speculation. Now the dust domains have yet to be shown to bind phosphotyrosineis settling, and a more enduring picture is beginning to containing peptides selectively. Nevertheless, the SH2 emerge as exemplified by two articles that deal with domain plays three important roles. It is critical for the STAT1 function in this issue of Cell (Durbin et al., 1996; recruitment of STATs to activated receptor complexes Meraz et al., 1996). This review provides a brief overview (detailed below). It is required for the interaction with of STAT structure, function, and possible evolution. Sevthe Janus protein-tyrosine kinases (JAKs), which phoseral reviews (Darnell et al., 1994; Schindler and Darnell, phorylate the STATs. Finally, the SH2 domain is required 1995; Ihle, 1995; Ihle and Kerr, 1995; Ihle et al., 1995) for STAT dimerization and the associated ability to bind provide more detail and, more importantly, references DNA. The STATs were also reported to contain SH3 to primary information. domains. This region is much less conserved, including STAT Family Members the critical residues involved in proline binding, and no The first STAT family members were identified as DNAevidence has emerged to suggest an SH3 function. binding proteins in interferon (IFN)-regulated gene ex-DNA binding by purified STAT1 is totally dependent pression. From these studies, two STATs and two disupon tyrosine phosphoryl...

Puma encodes a BH3-only protein that is induced by the p53 tumor suppressor and other apoptotic stimuli. To assess its physiological role in apoptosis, we generated Puma knockout mice by gene targeting. Here we report that Puma is essential for hematopoietic cell death triggered by ionizing radiation (IR), deregulated c-Myc expression, and cytokine withdrawal. Puma is also required for IR-induced death throughout the developing nervous system and accounts for nearly all of the apoptotic activity attributed to p53 under these conditions. These findings establish Puma as a principal mediator of cell death in response to diverse apoptotic signals, implicating Puma as a likely tumor suppressor.