Unphosphorylated STATs go nuclear

Brown, Stephen; Zeidler, Martin P.

doi:10.1016/j.gde.2008.09.002

Cited by 35 publications

(31 citation statements)

References 49 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it is noteworthy that U-STAT1 was also found persistently in the nucleus of epithelial cells as early described by the George Stark laboratory (45). Non-canonical STAT pathways employ STATs independently of tyrosine phosphorylation (21,46) . In general, pYSTAT1 signalling was found to be mostly associated with interferon signalling, whereas pYSTAT3 signalling is connected with responses emanating from the activated distal four tyrosine residues within the gp130 receptor cytoplasmic chain (43).…”

Section: Potential Role Of Non-phosphorylated Stats and Non-canonicalmentioning

confidence: 99%

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

Friedrich¹,

Dolznig

Han

et al. 2017

BST

View full text Add to dashboard Cite

Section: Potential Role Of Non-phosphorylated Stats and Non-canonicalmentioning

confidence: 99%

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

Friedrich¹,

Dolznig

Han

et al. 2017

BST

View full text Add to dashboard Cite

“…Drosophila, with its complete set of JAK/STAT components, provides a powerful genetic system to analyze the molecular functions of this essential pleiotropic pathway (for reviews, see Arbouzova and Zeidler, 2006;Brown and Zeidler, 2008;Müller et al, 2008). In addition to functions in embryonic, larval and imaginal development, JAK/STAT signaling is crucial for several steps of Drosophila oogenesis, including two distinct follicle cell specification events (Fig.…”

Section: Introductionmentioning

confidence: 99%

Glypicans regulate JAK/STAT signaling and distribution of the Unpaired morphogen

et al. 2012

View full text Add to dashboard Cite

SUMMARYIn Drosophila, ligands of the Unpaired (Upd) family activate the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. The JAK/STAT pathway controls many developmental events, including multiple functions in the ovary. These include an early role in the germarium for specification of stalk cells and a later role in the vitellarium to pattern the follicular epithelium surrounding each cyst. In this latter role, graded JAK/STAT activation specifies three distinct anterior follicular cell fates, suggesting that Upd is a morphogen in this system. Consistent with the JAK/STAT activation pattern in the vitellarium, Upd forms a concentration gradient on the apical surface of the follicular epithelium with a peak at its source, the polar cells. Like many morphogens, signaling and distribution of Upd are regulated by the heparan sulfate proteoglycans (HSPGs) Dally and Dally-like. Mutations in these glypican genes and in heparan sulfate biosynthetic genes result in disruption of JAK/STAT signaling, loss or abnormal formation of the stalk and significant reduction in the accumulation of extracellular Upd. Conversely, forced expression of Dally causes ectopic accumulation of Upd in follicular cells. Furthermore, biochemical studies reveal that Upd and Dally bind each other on the surface of the cell membrane. Our findings demonstrate that Drosophila glypicans regulate formation of the follicular gradient of the Upd morphogen, Upd. Furthermore, we establish the follicular epithelium as a new model for morphogen signaling in complex organ development.

show abstract

“…Previous studies using a Drosophila leukemia model have demonstrated a noncanonical mode of JAK/STAT signaling, in which the unphosphorylated form of STAT is localized in heterochromatin in association with HP1; STAT activation (by phosphorylation) causes its dispersal from heterochromatin, leading to HP1 delocalization and heterochromatin loss (9)(10)(11). Moreover, unphosphorylated STAT and heterochromatin are essential for maintaining genomic stability and counteracting aging in Drosophila (12,13).…”

mentioning

confidence: 99%

Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth

Dutta

Tsurumi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Tumor suppressors known to date impede cancer growth by arresting the cell cycle or promoting apoptosis. Here we show that unphosphorylated human STAT5A functions as a tumor suppressor capable of repressing multiple oncogenes via heterochromatin formation. Unphosphorylated STAT5A binds to heterochromatin protein 1α (HP1α) and stabilizes heterochromatin. Expressing unphosphorylated STAT5A or HP1α inhibits colon cancer growth in mouse xenograft models. Transcriptome profiling shows that expressing an unphosphorylatable STAT5A has similar effects to overexpressing HP1α in global gene expression. Notably, the majority of the genes commonly repressed by unphosphorylated STAT5A and HP1α have been implicated in cancer development. Finally, down-regulation, somatic mutations, and deletions of STAT5 genes are found in certain human cancers. These results suggest that unphosphorylated STAT5A may epigenetically suppress tumor growth by promoting heterochromatin formation.JAK/STAT | Drosophila | fluorescence recovery after photobleaching (FRAP) | transcription H eterochromatin plays a role in chromosomal compaction and transcriptional silencing and is emerging as a mechanism of tumor suppression. Certain tumor suppressors, such as breast cancer type 1 susceptibility protein (BRCA1) and the retinoblastoma protein (RB), have been shown to promote heterochromatin formation at specific loci or maintain the stability of constitutive heterochromatin (1-4). On the other hand, oncogenic JAK disrupts heterochromatin formation in both Drosophila and human cells (5, 6). In addition, a reduction in the levels of heterochromatin protein 1 (HP1), the major component and a determinant of heterochromatin (7), is associated with human cancer progression, including colon and breast cancers and leukemia (8). The target genes normally repressed by heterochromatin, however, have not been systematically investigated.Previous studies using a Drosophila leukemia model have demonstrated a noncanonical mode of JAK/STAT signaling, in which the unphosphorylated form of STAT is localized in heterochromatin in association with HP1; STAT activation (by phosphorylation) causes its dispersal from heterochromatin, leading to HP1 delocalization and heterochromatin loss (9-11). Moreover, unphosphorylated STAT and heterochromatin are essential for maintaining genomic stability and counteracting aging in Drosophila (12, 13). To investigate whether unphosphorylated STAT in mammals also promotes heterochromatin formation, and whether this constitutes a mechanism of tumor suppression, we examined the interaction between human STAT5A and HP1α (also known as "chromobox protein homolog 5," or CBX5) in human cells, tested their effects on tumorigenesis in mouse xenograft models, and examined their effects on global gene transcription by means of expression profiling. Results STAT5A and HP1αPhysically Interact. To test whether human STAT5A physically interacts with human HP1α, we used a series of plasmids to express HP1α-Flag and wild-type or mutant GFP-tagged STAT5A (...

show abstract

Unphosphorylated STATs go nuclear

Cited by 35 publications

References 49 publications

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

Glypicans regulate JAK/STAT signaling and distribution of the Unpaired morphogen

Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth

Contact Info

Product

Resources

About