Mutations of HNF-1β inhibit epithelial morphogenesis through dysregulation of SOCS-3

Ma, Zhendong; Gong, Yimei; Patel, Vishal; Karner, Courtney M.; Fischer, Evelyne; Hiesberger, Thomas; Carroll, Thomas J.; Pontoglio, Marco; Igarashi, Peter

doi:10.1073/pnas.0705957104

Cited by 61 publications

(61 citation statements)

References 39 publications

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“…9,11 However, the mechanism of STAT3 activation in renal cysts remained unknown. The observation that increased expression of SOCS3, an inhibitor of STAT3 activation, is associated with renal cyst growth in HNF-1b null mice 12 and human ADPKD ( Figure 1D) appeared to contradict a role of STAT3 in cyst growth. Moreover, our finding that wild-type, membrane-anchored PC1 can activate STAT3 via JAK2 4 might lead to the conclusion that the loss of functional PC1 in patients with ADPKD should lead to diminished STAT3 activity as opposed to the observed increased STAT3 activity.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the high expression levels of SOCS3 observed in human ADPKD here (Figure 1) and in renal cysts in HNF-1b null mice 12 would not be able to dampen STAT3 activated by this pathway. Interestingly, the high level of SOCS3 in renal cysts may be expected to suppress the response to cytokines that signal via receptors that are affected by SOCS3.…”

Section: Discussionmentioning

confidence: 99%

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The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Talbot¹,

Song²,

Wang³

et al. 2014

Journal of the American Society of Nephrology

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Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Srcdependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30-mediated activation of Src/ STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src/STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to cAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR-or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a proliferative response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Talbot¹,

Song²,

Wang³

et al. 2014

Journal of the American Society of Nephrology

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“…We previously identified PDE4C in a genome-wide screen for genes that were regulated by the transcription factor HNF-1β in the kidney (25). This result was of interest because mutations of HNF-1β produce kidney cysts in humans and mice (26,27).…”

Section: B Cmentioning

confidence: 99%

Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases

Choi¹,

Suzuki²,

Hajarnis³

et al. 2011

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

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114

115

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Polycystic kidney disease (PKD) is a genetic disorder that is characterized by cyst formation in kidney tubules. PKD arises from abnormalities of the primary cilium, a sensory organelle located on the cell surface. Here, we show that the primary cilium of renal epithelial cells contains a protein complex comprising adenylyl cyclase 5/6 (AC5/6), A-kinase anchoring protein 150 (AKAP150), and protein kinase A. Loss of primary cilia caused by deletion of Kif3a results in activation of AC5 and increased cAMP levels. Polycystin-2 (PC2), a ciliary calcium channel that is mutated in human PKD, interacts with AC5/6 through its C terminus. Deletion of PC2 increases cAMP levels, which can be corrected by reexpression of wild-type PC2 but not by a mutant lacking calcium channel activity. Phosphodiesterase 4C (PDE4C), which catabolizes cAMP, is also located in renal primary cilia and interacts with the AKAP150 complex. Expression of PDE4C is regulated by the transcription factor hepatocyte nuclear factor-1β (HNF-1β), mutations of which produce kidney cysts. PDE4C is down-regulated and cAMP levels are increased in HNF-1β mutant kidney cells and mice. Collectively, these findings identify PC2 and PDE4C as unique components of an AKAP complex in primary cilia and reveal a common mechanism for dysregulation of cAMP signaling in cystic kidney diseases arising from different gene mutations.

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“…S7), but regulation by miR-92 has not been studied. HNF-1β is an epithelial-specific transcription factor that regulates the expression of cystic disease genes, including Pkd2 and Pkhd1 (18,24,25). Polycystin-1, polycystin-2, and HNF-1β retard cell proliferation (25)(26)(27).…”

Section: Mir-17∼92 Promotes Proliferation and Regulates The Posttransmentioning

confidence: 99%

miR-17∼92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease

Patel¹,

Williams

Hajarnis

et al. 2013

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

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141

142

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Polycystic kidney disease (PKD), the most common genetic cause of chronic kidney failure, is characterized by the presence of numerous, progressively enlarging fluid-filled cysts in the renal parenchyma. The cysts arise from renal tubules and are lined by abnormally functioning and hyperproliferative epithelial cells. Despite recent progress, no Food and Drug Administration-approved therapy is available to retard cyst growth. MicroRNAs (miRNAs) are short noncoding RNAs that inhibit posttranscriptional gene expression. Dysregulated miRNA expression is observed in PKD, but whether miRNAs are directly involved in kidney cyst formation and growth is not known. Here, we show that miR-17∼92, an oncogenic miRNA cluster, is up-regulated in mouse models of PKD. Kidney-specific transgenic overexpression of miR-17∼92 produces kidney cysts in mice. Conversely, kidney-specific inactivation of miR-17∼92 in a mouse model of PKD retards kidney cyst growth, improves renal function, and prolongs survival. miR-17∼92 may mediate these effects by promoting proliferation and through posttranscriptional repression of PKD genes Pkd1, Pkd2, and hepatocyte nuclear factor-1β. These studies demonstrate a pathogenic role of miRNAs in mouse models of PKD and identify miR-17∼92 as a therapeutic target in PKD. Our results also provide a unique hypothesis for disease progression in PKD involving miRNAs and regulation of PKD gene dosage.cilia | kinesin family member 3A | autosomal dominant polycystic kidney disease P olycystic kidney disease (PKD) is among the most common monogenic human diseases (1, 2). PKD is characterized by the presence of numerous fluid-filled cysts in the renal parenchyma. The cysts arise from renal tubules and are lined by abnormally functioning epithelial cells. The cyst epithelial cells secrete excessive fluid and display high rates of proliferation, which results in cyst expansion. The expanding cysts compress the surrounding normal nephrons, which cause renal failure. Based on the mode of inheritance, PKD is classified into autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD). ADPKD is caused by mutations of PKD1 or PKD2, which encode polycystin-1 and polycystin-2, respectively. ARPKD is caused by mutations of polycystic kidney and hepatic disease 1 (PKHD1) which encodes fibrocystin (1, 3). Polycystin-1, polycystin-2, and fibrocystin localize to the primary cilium, a sensory organelle present on the apical surface of most cells in the body. Abnormalities of the primary cilium are linked to the pathogenesis of many forms of cystic kidney diseases, including PKD (1, 4, 5). Despite recent advances, no Food and Drug Administration-approved therapy is available for PKD patients.MicroRNAs (miRNAs) are noncoding RNAs that constitute the endogenous RNA interference pathway. miRNAs are transcribed as primary miRNAs (pri-miRNAs), which are sequentially processed by the enzymes Drosha and Dicer to produce mature miRNAs (6). Watson-Crick base pairing between nucleotides 2-8 (seed sequence) at the 5′ end of the matur...

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Mutations of HNF-1β inhibit epithelial morphogenesis through dysregulation of SOCS-3

Cited by 61 publications

References 39 publications

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases

miR-17∼92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease

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