Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis (original) (raw)
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STAT PROTEINS: NOVEL MOLECULAR TARGETS FOR CANCER DRUG DISCOVERY
Vectors of Transcription (STATs) are a family of cytoplasmic proteins with roles as signal messengers and transcription factors that participate in normal cellular responses to cytokines and growth factors. Compared with normal cells and tissues, constitutively activated STATs have been detected in a wide variety of human cancer cell lines and primary tumors. In tumor cells, constitutive activation of STATs is linked to persistent activity of tyrosine kinases, including Src, epidermal growth factor receptor, Janus kinases, Bcr-Abl, and many others. Such oncogenic tyrosine kinases are often activated as a consequence of permanent ligand/receptor engagement in autocrine or paracrine cytokine and growth factor signaling or represent autonomous constitutively active enzymes as a result of genetic alterations found in tumor but not normal cells. Frequently, however, abnormal activity of certain STAT family members, particularly Stat3 and Stat5, is associated with a wide variety of human malignancies, including hematologic, breast, head and neck, and prostate cancers by stimulating cell proliferation and preventing apoptosis. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signaling as therapeutics continue. Constitutive activation of Stat3 signaling is accompanied by upregulation of cyclin D1, c-Myc, and Bcl-x, changes consistent with subversion of normal cellular growth and survival control mechanisms. Application of molecular biology and pharmacology tools in disease relevant models has confirmed Stat3 as having a causal role in oncogenesis, and provided validation of Stat3 as a target for cancer drug discovery and therapeutic intervention. Inhibition of constitutively active STAT signaling pathways has been confirmed to inhibit tumor cell growth in vitro and in vivo and provides a novel means for therapeutic intervention in human cancer. Keywords: STAT proteins, tyrosine kinases, signaling, cancer, therapeutics
STAT proteins: from normal control of cellular events to tumorigenesis
Journal of cellular physiology, 2003
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 IFNgamma signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in ...
Clinical cancer research, 2002
The signal transducers and activators of transcription (STAT) factors function as downstream effectors of cytokine and growth factor receptor signaling. Compared with normal cells and tissues, constitutively activated STATs have been detected in a wide variety of human cancer cell lines and primary tumors. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulated process. In tumor cells, constitutive activation of STATs is linked to persistent activity of tyrosine kinases, including Src, epidermal growth factor receptor, Janus kinases, Bcr-Abl, and many others. Such oncogenic tyrosine kinases are often activated as a consequence of permanent ligand/receptor engagement in autocrine or paracrine cytokine and growth factor signaling or represent autonomous constitutively active enzymes as a result of genetic alterations found in tumor but not normal cells. Persistent signaling of specific STATs, in particular Stat3 and Stat5, has been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis. STATs participate in oncogenesis through up-regulation of genes encoding apoptosis inhibitors and cell cycle regulators such as Bcl-x L , Mcl-1, cyclins D1/D2, and c-Myc. Inhibition of constitutively active STAT signaling pathways has been shown repeatedly to inhibit tumor cell growth in vitro and in vivo and provides a novel means for therapeutic intervention in human cancer. In this review, we will: (a) explain the mechanisms of STAT activation in normal and malignant signaling; (b) summarize recent evidence for the critical role of constitutively activated Stat3 and Stat5 in oncogenesis; (c) identify candidate STAT target genes implicated in tumor progression; and (d) discuss molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in human cancer.
Rare mutations provide unique insight into oncogenic potential of STAT transcription factors
The Journal of clinical investigation, 2018
The inappropriate activation of transcription factors, including STATs, is known to promote tumor initiation and progression. The most common mechanisms of misregulation lead to constitutive activation of WT STATs. However, the recent discovery of rare STAT mutations in hematopoietic malignancies suggests that STAT mutants may be oncogenic. In this issue of the JCI, Pham et al. use a transgenic mouse model to demonstrate that STAT5BN642H is sufficient for the development of T cell neoplasia. This study, along with other studies of constitutively active STAT mutants, provides insight into the pathogenesis and treatment of STAT5-driven cancer.
Targeting Oncogenic Transcription Factors: Therapeutic Implications of Endogenous STAT Inhibitors
Trends in cancer, 2017
Misregulation of transcription factors, including signal transducer and activator of transcription (STAT) proteins, leads to inappropriate gene expression patterns that can promote tumor initiation and progression. Under physiologic conditions, STAT signaling is stimulus dependent and tightly regulated by endogenous inhibitors, namely, suppressor of cytokine signaling (SOCS) proteins, phosphatases, and protein inhibitor of activated STAT (PIAS) proteins. However, in tumorigenesis, STAT proteins become constitutively active and promote the expression of progrowth and prosurvival genes. Although STAT activation has been widely implicated in cancer, therapeutic STAT inhibitors are still largely absent from the clinic. This review dissects the mechanisms of action of two families of endogenous STAT inhibitors, the SOCS and PIAS families, to potentially inform the development of novel therapeutic inhibitors.
STAT Signaling in Cancer: Insights into Pathogenesis and Treatment Strategies
The inappropriate survival and proliferation of cancer cells often arises from the activation of signaling pathways normally under the control of physiologic stimuli. The genetic alterations which occur in a tumor cell lead to the inappropriate activation of these signaling pathways, resulting in the persistent survival or growth of cells independent of the appropriate cues. A pathway which has been found to be important in mediating the effects of many physiologic stimuli is the STAT pathway. Originally identified as playing a key role in hematologic and immune cells, STATs are now recognized to play a prominent role in transducing signals from a wide variety of stimuli, in perhaps every tissue in the body. Given this prominent role in normal homeostasis, it is not surprising that STATs have been found to be activated inappropriately in a wide array of human cancers. This has provided important information about the molecular pathogenesis of cancer, and presents possible strategies...