STAT proteins: From normal control of cellular events to tumorigenesis

Abstract

Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors latent in the cytoplasm that participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis, and angiogenesis following cytokine, growth factor, and hormone signaling. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulates process. Nevertheless, several constitutively activated STATs have been observed in a wide number of human cancer cell lines and primary tumors, including blood malignancies and solid neoplasias. STATs can be divided into two groups according to their specific functions. One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T-cells and in IFNg signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in IFN signaling, development of the mammary gland, response to GH, and embriogenesis. This latter group of STATS plays an important role in controlling cell-cycle progression and apoptosis and thus contributes to oncogenesis. Although an increased expression of STAT1 has been observed in many human neoplasias, this molecule can be considered a potential tumor suppressor, since it plays an important role in growth arrest and in promoting apoptosis. On the other hand, STAT3 and 5 are considered as oncogenes, since they bring about the activation of cyclin D1, c-Myc, and bcl-xl expression, and are involved in promoting cell-cycle progression, cellular transformation, and in preventing apoptosis.

Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma

“…19,20 Stat5 has also been shown to contribute to the oncogenesis of human breast carcinoma by playing an important role in controlling cell-cycle progression and apoptosis. 21 Given these data, one hypothesis to be tested was that the expression of Vav2 would increase in malignant tissues as compared to benign tissues in response to its increased role of stimulating Rac1 and Stat5-mediated gene transcription in breast cancer. Although the visual scoring data disagreed with our hypothesis by showing a decrease in the expression of Vav2, the data did not achieve statistical significance (P ¼ 0.107).…”

“…25,26 It is suggested that these Stat proteins participate in oncogenesis through the upregulation of genes encoding for cell-cycle regulators (cyclin D1, c-Myc), apoptosis inhibitors (Bcl-z, Mcl-1), and inducers of angiogenesis (VEGF). 21 Recent studies have focused on the quantitative expression of Stats in malignant breast tissues to provide support for the association between Stat function and oncogenesis. 9 Our study examined the expression of positive and negative regulators of Stat5.…”

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

“…The expression of signal transducer and activator of transcription 1 (STATl) was also observed to be highly correlated to resistance, particularly for the Top2 inhibitors (data not shown). Although activation of STATl in some cell systems has been shown to be proapoptotic (Calo et al, 2003), a recent observation has indicated a role for STATl in mediating radiation resistance (Khodarev et al, 2004). Recently, a correlation between STATl expression and cisplatin resistance in cell lines derived from patients with ovarian carcinoma was also reported (Roberts et al, 2005), and inhibitors of the STATl pathway have been shown to induce apoptosis in leukaemic cells from patients (Martinez-Lostao et al, 2005).…”

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

“…key protein kinases that phosphorylates Stat3 at S727 (Calo et al, 2003;Clevenger, 2004;Yonezawa et al, 2004). We thereby examined Stat3 phosphorylation on S727 using Western blotting.…”