Mesenchymal to Epithelial Conversion in Rat Metanephros Is Induced by LIF

Barasch, Jonathan; Yang, Jun; Ware, Carol B.; Taga, Tetsuya; Yoshida, Kanji; Erdjument‐Bromage, Hediye; Tempst, Paul; Parravicini, Elvira; Malach, Stephen; Aranoff, Tsvi; Oliver, Juan A.

doi:10.1016/s0092-8674(00)81524-x

Cited by 248 publications

(176 citation statements)

References 64 publications

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“…Another question that remains is how Wnt signaling relates to the activity of other factors that appear to be sufficient for kidney tubule formation, including the leukemia inhibitory factor (Lif) and transforming growth factor beta (TGFβ) [48,49]. Previous studies have shown that, similarly to Wnt9b and Wnt4, both of these factors weakly induce canonical Wnt signaling in isolated mesenchyme.…”

Section: Wnts In Renal Vesicle Formationmentioning

confidence: 99%

Molecular regulation of kidney development: is the answer blowing in the Wnt?

2007

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Development of the metanephric kidney is a complicated process regulated by reciprocal signals from the ureteric bud and the metanephric mesenchyme that regulate tubule formation and epithelial branching morphogenesis. Over the past several years, several studies have suggested that Wnt signaling is involved in multiple aspects of normal kidney development as well as injury response and cancer progression. We will review these data here.

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Section: Wnts In Renal Vesicle Formationmentioning

confidence: 99%

Molecular regulation of kidney development: is the answer blowing in the Wnt?

2007

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“…Leukemia inhibitory factor and the associated transient activation of STAT proteins has been implicated in inducing conversion of metanephric mesenchyme/blastema to podocytes and epithelial tubules of the nephron (Barasch et al, 1999;Plisov et al, 2001). We, therefore, hypothesized that abnormal constitutive activation of STATs in metanephric mesenchyme may lead to the deregulation of the differentiation program, resulting in renal tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3 0 -kinase, protein kinase C or Ca/calmodulindependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.

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“…LIF is a 40-45 kDa monomeric glycoprotein belonging to the IL6 family of cytokines. It is a pleiotropic molecule known to induce differentiation of mouse myeloid leukaemic cells [17], regeneration of muscle [18] and nerve [19], and mesenchymal-to-epithelial transdifferentiation in the developing kidney [20], whereas it inhibits differentiation and promotes proliferation of embryonic stem cells [21]. The action of LIF is mediated by a functional LIF receptor composed of two signal-transducing proteins, LIF receptor-β (LIFR) and gp130.…”

Section: Introductionmentioning

confidence: 99%

Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas

2005

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Aims/hypothesis: It was recently reported that culturing adult exocrine cells in the presence of epidermal growth factor and leukaemia inhibitory factor (LIF) resulted in their transdifferentiation into endocrine beta cells. The aim of this study was to examine the expression and function of LIF in the pancreas. Materials and methods: We studied the expression of LIF and its receptor components, LIF-receptor-β and gp130, by immunohistochemistry, western blotting and RT-PCR in normal rat pancreas, pancreas with duct ligation-induced islet neogenesis, and in pancreatic cell cultures. Isolated duct fragments were cultured in the presence of LIF and a janus kinase 2 (JAK2) inhibitor. Results: LIF was detected by immunohistochemistry, western blot and RT-PCR in the ducts of the normal pancreas. Both LIF-receptor-β and gp130 were detected by RT-PCR in the pancreas. Immunostaining revealed gp130 exclusively in the ducts and centro-acinar cells. After duct ligation-induced tissue injury, upregulation of LIF and its receptor occurred in rat pancreas. Metaplastic exocrine cells also started to express LIF and this was increased after alloxan treatment. Signalling via LIF-receptor-β/gp130 involves the JAK/signal transducer and activator of transcription (STAT) pathway. LIF induced increased activation of STAT3 in pancreatic cells. In isolated duct fragments, addition of LIF resulted in a significant increase in duct cell proliferation, while a specific inhibitor of the JAK/STAT signalling pathway inhibited proliferation. Conclusion/interpretation: Our observations show that LIF and its receptor are expressed in cells from pancreatic ducts. The cytokine plays a role in pancreatic physiology, controls duct cell proliferation and is involved in repair processes following pancreatic injury.

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Mesenchymal to Epithelial Conversion in Rat Metanephros Is Induced by LIF

Cited by 248 publications

References 64 publications

Molecular regulation of kidney development: is the answer blowing in the Wnt?

Molecular regulation of kidney development: is the answer blowing in the Wnt?

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas

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