An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1

Kim, Marianne K.H.; McGarry, Thomas J.; Broin, Pilib Ó; Flatow, Jared; Golden, Aaron; Licht, Jonathan D.

doi:10.1073/pnas.0901591106

Cited by 70 publications

(65 citation statements)

References 44 publications

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“…Of interest, loss of WT1, in turn, is able to amplify b-catenin signaling, because WT1 is a negative inhibitor of Wnt/b-catenin signaling. 40,41 Therefore, b-catenin activation and loss of WT1 effectively form a feed-forward vicious cycle, leading to exaggerated podocyte injury ( Figure 5I). …”

Section: Discussionmentioning

confidence: 99%

Mutual Antagonism of Wilms’ Tumor 1 and β-Catenin Dictates Podocyte Health and Disease

Zhou

Li²,

He³

et al. 2015

Journal of the American Society of Nephrology

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Activation of b-catenin, the intracellular mediator of canonical Wnt signaling, has a critical role in mediating podocyte injury and proteinuria. However, the underlying mechanisms remain poorly understood. Here, we show that b-catenin triggers ubiquitin-mediated protein degradation of Wilms' tumor 1 (WT1) and functionally antagonizes its action. In mice injected with adriamycin, WT1 protein was progressively lost in glomerular podocytes at 1, 3, and 5 weeks after injection. Notably, loss of WT1 apparently did not result from podocyte depletion but was closely associated with upregulation of b-catenin. This change in WT1/ b-catenin ratio was accompanied by loss of podocyte-specific nephrin, podocalyxin, and synaptopodin and acquisition of mesenchymal markers Snail1, a-smooth muscle actin, and fibroblast-specific protein 1. In vitro, overexpression of b-catenin induced WT1 protein degradation through the ubiquitin proteasomal pathway, which was blocked by MG-132. WT1 and b-catenin also competed for binding to common transcriptional coactivator CREB-binding protein and mutually repressed the expression of their respective target genes. In glomerular miniorgan culture, activation of b-catenin by Wnt3a repressed WT1 and its target gene expression. In vivo, blockade of Wnt/b-catenin signaling by endogenous antagonist Klotho induced WT1 and restored podocyte integrity in adriamycin nephropathy. These results show that b-catenin specifically targets WT1 for ubiquitin-mediated degradation, leading to podocyte dedifferentiation and mesenchymal transition. Our data also suggest that WT1 and b-catenin have opposing roles in podocyte biology, and that the ratio of their expression levels dictates the state of podocyte health and disease in vivo.

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Section: Discussionmentioning

confidence: 99%

Mutual Antagonism of Wilms’ Tumor 1 and β-Catenin Dictates Podocyte Health and Disease

Zhou

Li²,

He³

et al. 2015

Journal of the American Society of Nephrology

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“…Since the crystal structure of the KLF4 protein has not yet been determined, it is not clear if KLF4 interfaces with ␤-catenin in a similar manner. Recently, it was reported that WT1, another C 2 H 2 zinc finger protein, competes with TCF4 for CBP binding and thus inhibits Wnt signaling (23). Since KLF4 also binds p300/CBP (9), KLF4 may compete with ␤-catenin/TCF4 for p300/CBP binding as well.…”

Section: Discussionmentioning

confidence: 99%

KLF4 Interacts with β-Catenin/TCF4 and Blocks p300/CBP Recruitment by β-Catenin

Evans

Chen

Zhang

et al. 2010

Molecular and Cellular Biology

106

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Wnt signaling is crucial in the organization and maintenance of the human intestinal epithelium, and somatic mutations that result in deregulated Wnt signaling are an early event in the development of colorectal cancer. The Wnt ligand ultimately results in the stabilization of cytoplasmic ␤-catenin, which is then free to enter the nucleus and activate transcription through its interaction with the transcription factor TCF4. Our laboratory recently found that KLF4, a transcription factor highly expressed in the adult intestine and critical for intestinal differentiation, interacts with ␤-catenin and inhibits Wnt signaling. In this study, we characterize the molecular mechanisms of KLF4-mediated inhibition of Wnt/␤-catenin signaling. We find that the KLF4 directly interacts with the C-terminal transactivation domain of ␤-catenin and inhibits p300/CBP recruitment by ␤-catenin. KLF4 inhibits p300/CBP-mediated ␤-catenin acetylation as well as histone acetylation on Wnt target genes. In addition, we observe that KLF4 directly interacts with TCF4 independently of ␤-catenin and that KLF4 and TCF4 are expressed in similar patterns within the large intestine, with greatest staining near the epithelial surface. These results provide a deeper understanding of the regulation of ␤-catenin in the intestine and will have important implications in cancer and stem cell research.The Wnt/␤-catenin signaling pathway plays important roles in early development (19, 31), stem cell renewal (22,34), and tumorigenesis (20,35). In addition, Wnt signaling is crucial in the organization and maintenance of the human intestinal epithelium (46, 51), and somatic mutations that result in deregulated Wnt signaling are an early event in the development of colorectal cancer (37,39,47). In this pathway, many different components work together to transduce an external signal into changes in gene expression within the target cell. Upon binding its receptor, the Wnt ligand ultimately results in the stabilization of cytoplasmic ␤-catenin (44), which is then free to enter the nucleus and activate transcription through its interaction with the TCF/LEF family of transcription factors (1,18,36).In the adult intestine, TCF4 is the primary TCF/LEF family member involved in mediating active Wnt/␤-catenin signaling (25,26). In contrast, TCF1 and TCF3 are primarily transcriptional repressors (14, 49), whereas LEF1 is not expressed in the adult intestine (59). In the absence of ␤-catenin, TCF4 recruits corepressors such as CtBP (4), HDAC1 (3, 24), and Groucho/ TLE (5, 28, 50), in order to silence expression of target genes. However, binding of ␤-catenin results in displacement of these corepressors (7). ␤-Catenin then recruits coactivators through its N-terminal and C-terminal transactivation domains. Its Nterminal transactivation domain interacts with BCL9/Legless, which in turn recruits Pygopus (2, 27, 45, 55), whereas its C-terminal domain recruits p300/CBP. p300 and CBP are closely related proteins that promote transcriptional activation through several mechan...

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“…b-catenin/Wnt signaling, which represents a pivotal step driving PEC differentiation into podocytes during kidney development [7]. Indeed, conditional b-catenin-knockout mice in which Ctnnb1 (mouse b-catenin gene) was removed during later stages of nephrogenesis in PECs show underdeveloped glomerular capillary tufts, with podocytes replacing normal flat PECs.…”

Section: Role In Normal Glomerular Developmentmentioning

confidence: 99%

Glomerular parietal epithelial cells in kidney physiology, pathology, and repair

Shankland

Anders

Romagnani

2013

Current Opinion in Nephrology and Hypertension

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Purpose of reviewWe have summarized recently published glomerular parietal epithelial cell (PEC) research, focusing on their roles in glomerular development and physiology, and in certain glomerular diseases. The rationale is that PECs have been largely ignored until the recent availability of cell lineage tracing studies, human and murine PEC culture systems, and potential therapeutic interventions of PECs. Recent findingsSeveral new paradigms involving PECs have emerged demonstrating their significant contribution to glomerular physiology and numerous glomerular diseases. A subset of PECs serving as podocyte progenitors have been identified in normal human glomeruli. They provide a source for podocytes in adolescent mice, and their numbers increase in states of podocyte depletion. PEC progenitor number is increased by retinoids and angiotensin-converting enzyme inhibition. However, dysregulated growth of PEC progenitors leads to pseudo-crescent and crescent formation. In focal segmental glomerulosclerosis, considered a podocyte disease, activated PECs increase extracellular matrix production, which leads to synechial attachment and, when they move to the glomerular tuft, to segmental glomerulosclerosis. Finally, PECs might be adversely affected in proteinuric states by undergoing apoptosis. SummaryPECs play a critical role in glomerular repair through their progenitor function, but under certain circumstances paradoxically contribute to deterioration by augmenting scarring and crescent formation.

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An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1

Cited by 70 publications

References 44 publications

Mutual Antagonism of Wilms’ Tumor 1 and β-Catenin Dictates Podocyte Health and Disease

Mutual Antagonism of Wilms’ Tumor 1 and β-Catenin Dictates Podocyte Health and Disease

KLF4 Interacts with β-Catenin/TCF4 and Blocks p300/CBP Recruitment by β-Catenin

Glomerular parietal epithelial cells in kidney physiology, pathology, and repair

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