Roles and regulation of stat family transcription factors in human breast cancer

Abstract

Stats (for signal transducers and activators of transcription) are a family of transcription factors that regulate cell growth and differentiation. Their activity is latent until phosphorylation by receptor-associated kinases. A sizable body of data from cell lines, mouse models, and human tissues now implicates these transcription factors in the oncogenesis of breast cancer. Because Stat activity is modulated by several posttranslational modifications and protein-protein interactions, these transcription factors are capable of integrating inputs from multiple signaling networks. Given this, the future utilization of Stats as prognostic markers and therapeutic targets in human breast cancer appears likely.

Figure 1

Activation and regulation of Stat-mediated transcription. After ligand-induced receptor dimerization, activated Jak sequentially phosphorylates receptor and Stat. This induces the release and dimerization of phosphorylated Stat, enabling its translocation into the nucleus and subsequent DNA binding. As indicated in the figure, Stat activity is regulated at many levels; events that stimulate Stat activity are noted with lines terminating in arrowheads, whereas inhibitory events are marked with lines ending with bars. Abbreviations: ub, ubiquitin; pY, phosphotyrosine; PTP, phosphatase. For the sake of simplicity some Stat regulatory events (ie, serine phosphorylation, protein-protein interactions, and so forth) have been omitted.

Figure 2

Structural maps of the Stat, SOCS, SHP, and PIAS protein families. Phosphorylated tyrosine and serine residues implicated in protein function are, respectively, designated pY and pS. The phosphatase domain is noted in the C-terminus of SHP (PTP). The signature leucine-rich motif conserved in the PIAS family is designated in the N-terminus of PIAS3 (LXXLL).

Figure 3

Mechanism for PRL/CypB induction of Stat5-induced gene expression. After receptor-mediated endocytosis, the transport of PRL into the nucleus is facilitated by its interaction with CypB. On entry into the nucleus, this complex interacts with Stat5 inducing the release of a repressor of its DNA-binding activity, namely PIAS3. The PRL/CypB-mediated release of PIAS3 from Stat5 results in significantly enhanced gene expression. Abbreviations: Pol, RNA polymerase II transcriptional apparatus; Sec61, ER transporter apparatus.