Review
The Stat family in cytokine signaling

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Abstract

During the past few years studies from several laboratories have utilized gene disruption approaches to define the function of members of the Stat family of transcription factors. The results have demonstrated that each family member has unique, critical, non-redundant functions in signal transduction through members of the cytokine receptor superfamily. Many of the family members mediate functions associated with innate or acquired immunity. With the availability of mice deficient in one or more of the Stats, critical experiments are possible to evaluate the roles of Stat signal transduction pathways in cellular transformation as well as evaluating their specific roles in a range of cellular responses to cytokines.

Introduction

The signal transducers and activators of transcription (Stat) family of transcription factors was first identified through the biochemical purification of factors involved in interferon (IFN)-regulated gene expression [1]. Additional family members were identified by screening ESTs for related genes or by purification of DNA-binding activities induced by cytokines. Numerous reviews have appeared on Stats including 2., 3., 4., 5., 6., 7., 8.. More recently, an entire issue of Oncogene reviews [9] appeared that was dedicated to the Stat family. Consequently, this review will provide an overview of essential, definitive properties of the Stats and focus on a few of the controversies that currently exist.

Section snippets

The Stat family

The Stat family consists of seven members (Table 1) that are genetically localized to three chromosomal regions [10]. The distribution of the genes suggests that an initial Stat gene, or genomic region, underwent duplication; this duplication was further duplicated to give the three current genetic loci containing the Stat genes. More recently, a duplication of the Stat5 gene occurred on chromosome 11 to give rise to the highly related Stat5a and Stat5b genes. Although the orientations of most

Stat1

The physiological functions of the Stat proteins have been studied in numerous cell systems; however, mouse strains in which each of the Stat family members have been deleted have proved to be particularly useful. In contrast to many of the studies with cell systems, mice knockouts have demonstrated a remarkable specificity of function for the Stat proteins (Table 1). The first strains of mice to be generated were those lacking Stat1 15., 16.. These mice are viable and display no developmental

Stat2

Stat2 is almost uniquely tyrosine phosphorylated and activated in the presence of IFNα/β—cytokines that activate the ISGF-3 complex, which consists of Stat1, Stat2 and p48. Recently, mice lacking Stat2 have been generated (C Park, S Li, E Cha, C Schindler, personal communication). As with Stat1 deficient mice, these mice are viable and develop normally. However, similar to Stat1 deficient mice, Stat2 null mice are susceptible to viral infections, and cells from these mice are unresponsive to

Stat4 and Stat6

Stat4 and Stat6 have strikingly specific physiological functions, as revealed by knockout mice. Stat4 is predominantly activated in response to IL-12, a macrophage-derived cytokine that is critical for controlling T helper cell differentiation along the Th1 pathway. The phenotype of the mice is very similar, if not identical, to that of mice lacking IL-12 19., 20.. Stat6 is primarily activated by IL-4 and the highly related cytokine IL-13. As expected, Stat6 deficient mice lack most of the

Stat3

The functions of Stat3 have been more difficult to define from knockout mice studies as the embryos die early in embryogenesis prior to gastrulation [23]. The timing of the lethality and the high level of expression of Stat3 in the extraembryonic visceral endoderm suggest that extraembryonic cells are unable to initiate the implantation or provide the nutritional support necessary for viable mice [24]. If this is right, the early embyronic lethality should be corrected by using a tetraploid

Stat5 proteins

Unlike most of the Stats, the two highly related Stat5 proteins are activated in response to a variety of cytokines as well as tyrosine kinase receptors. Therefore, it was assumed that Stat5a/b would have very basic functions in regulating cell growth. However, mice lacking Stat5a [33], Stat5b [34] or Stat5a/b [35] indicated specific functions for these proteins. Stat5a deficiency results in the loss of prolactin-dependent mammary gland development, which is necessary for lactation. Deleting

Conclusions

The physiological role of the individual members of the mammalian Stat family of transcription factors are being defined from analysis of mutant strains of mice lacking one or more family members. To date, the results have defined very discreet physiological roles for each of the family members. It is particularly striking to compare the role of Stat5a/b in the context of Epo, Tpo, growth hormone and prolactin activity, as their receptors are virtually identical, both structurally and

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • radical dot of special interest

  • radical dotradical dot of outstanding interest

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