Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

Taylor, Michael D.; Zhang, Xiaoyun; Liu, Ling; Hui, Chi‐chung; Mainprize, Todd G.; Scherer, Stephen W.; Wainwright, Brandon; Hogg, David; Rutka, James T.

doi:10.1038/sj.onc.1207605

Cited by 76 publications

(43 citation statements)

References 52 publications

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“…The recent findings that negative regulators of Shh pathway, Supressor of Fused (Sufu) and repressor isoforms of Gli3, antagonise Wnt signaling have begun to suggest an explanation. [119][120][121] Strikingly, canonical Wnt signalling is reduced in the dorsal neural tube in the absence of Shh. This inhibition is rescued in Shh -/-,Gli3 -/-mice suggesting that inhibitory Gli activity blocks canonical Wnt signalling.…”

Section: Shh Is a Mitogenic And Survival Factor In The Cnsmentioning

confidence: 99%

“…Consistent with this, Sufu interacts with b-catenin. 119,120 Whether this interaction is direct or via other proteins, such as Gli proteins, remains to be determined. Moreover whether the inhibitory activity of Sufu on Wnt-b-catenin signalling is regulated by Shh signaling has not been established and the role that Sufu might have in the Gli3R-b-catenin interaction needs to be evaluated.…”

Section: Shh Is a Mitogenic And Survival Factor In The Cnsmentioning

confidence: 99%

“…Although the mechanistic details of this effect have to be determined, Gli3 physically interacts with b-catenin, suggesting the possibility that Gli3 exerts its inhibitory action by recruiting co-repressors or by displacing b-catenin co-activators. 121 Experimental evidence indicates that another negative regulator of Shh pathway, the protein Sufu, also inhibits Wnt-b-catenin pathway 119,120 possibly by sequestering b-catenin in the cytoplasm. Consistent with this, Sufu interacts with b-catenin.…”

Section: Shh Is a Mitogenic And Survival Factor In The Cnsmentioning

confidence: 99%

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Morphogens and the Control of Cell Proliferation and Patterning in the Spinal Cord

Ulloa¹,

Briscoe²

2007

Cell Cycle

181

137

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The development of animal embryos depends on accurate coordination of the growth and specification of precursor cells. Morphogens, extracellular signals that act at a distance to control cell fate, are crucial in the patterning of embryonic tissues. One of the most extensively studied examples of a morphogen patterned tissue is the developing vertebrate spinal cord. The distribution of distinct neuronal subtypes along the dorsoventral (DV) axis of the spinal cord is determined by counteracting gradients of long-range signals. Wnt and BMP signals promote dorsal identities, while Shh signaling induces ventral identities. Simultaneous to their specification, neural progenitors proliferate, facilitating the growth of the neural tube. In this review we discuss evidence indicating that the signals governing progenitor specification also control proliferation and survival of progenitor cells. Moreover, evidence of reciprocal transcriptional interactions and cross-talk between the signaling pathways has emerged from recent studies. Together these studies suggest ways in which patterning and growth may be coordinated in the spinal cord. One level of interaction is an inhibitory regulation of repressor forms of the transcription factor Gli3-generated in the absence of Shh-on b-catenin activity, the transcription factor activated by Wnt signaling. This interaction may also be relevant in other tissues and situations in which the two signaling pathways are known to participate.

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Section: Shh Is a Mitogenic And Survival Factor In The Cnsmentioning

confidence: 99%

Section: Shh Is a Mitogenic And Survival Factor In The Cnsmentioning

confidence: 99%

Section: Shh Is a Mitogenic And Survival Factor In The Cnsmentioning

confidence: 99%

See 1 more Smart Citation

Morphogens and the Control of Cell Proliferation and Patterning in the Spinal Cord

Ulloa¹,

Briscoe²

2007

Cell Cycle

181

137

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“…We focused on genes that appeared in both the ChIP-on-chip screen and an ongoing profiling study comparing the mRNA expression changes in NPCs forced to express Sox10, Mash1, or Neurogenin2. Among the genes found to have both predicted Sox10-binding sites and significant changes in mRNA levels after Sox10 expression was a well-established regulator of multiple morphogenic signaling pathways-Suppressor of Fused (Sufu) (21)(22)(23)(24)(25) (Fig. 2).…”

Section: Sufu Is a Predicted Direct Target Of Sox10 And Is Down-regulmentioning

confidence: 99%

Sox10 directs neural stem cells toward the oligodendrocyte lineage by decreasing Suppressor of Fused expression

Pozniak¹,

Langseth

Dijkgraaf³

et al. 2010

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

106

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Oligodendrocyte precursor cells (OPCs) are lineage-restricted progenitors generally limited in vivo to producing oligodendrocytes. Mechanisms controlling genesis of OPCs are of interest because of their importance in myelin development and their potential for regenerative therapies in multiple sclerosis and dysmyelinating syndromes. We show here that the SoxE transcription factors (comprising Sox8, 9, and 10) induce multipotent neural precursor cells (NPCs) from the early postnatal subventricular zone (SVZ) to become OPCs in an autonomous manner. We performed a chromatin immunoprecipitation-based bioinformatic screen and identified Suppressor of Fused (Sufu) as a direct target of repression by Sox10. In vitro, overexpression of Sufu blocked OPC production, whereas RNAi-mediated inhibition augmented OPC production. Furthermore, mice heterozygous for Sufu have increased numbers of OPCs in the telencephalon during development. We conclude that Sox10 acts to restrict the potential of NPCs toward the oligodendrocyte lineage in part by regulating the expression of Sufu.

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“…We, also observed lowered BCL2 expression levels in the epidermis of DNp63a BG mice. In addition, SUFU is a negative regulator of b-catenin, 46 and analysis of the DNp63a BG mice indicated a suppressed b-catenin/WNT axis. 31 This SUFU-mediated downturn in HH and WNT activity results in depletion of stem cells and also hair loss.…”

Section: Discusssionmentioning

confidence: 99%

Interaction between the TP63 and SHH pathways is an important determinant of epidermal homeostasis

Chari¹,

Romano

et al. 2013

Cell Death Differ

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Deregulation of the hedgehog (HH) pathway results in overexpression of the GLI target BCL2 and is an initiating event in specific tumor types including basal cell carcinoma of the skin. Regulation of the HH pathway during keratinocyte differentiation is not well understood. We measured HH pathway activity in response to differentiation stimuli in keratinocytes. An upregulation of suppressor of fused (SUFU), a negative regulator of the HH pathway, lowered HH pathway activity and was accompanied by loss of BCL2 expression associated with keratinocyte differentiation. We used in vitro and in vivo models to demonstrate that DNp63a, a crucial regulator of epidermal development, activates SUFU transcription in keratinocytes. Increasing SUFU protein levels inhibited GLI-mediated gene activation in suprabasal keratinocytes and promoted differentiation. Loss of SUFU expression caused deregulation of keratinocyte differentiation and BCL2 overexpression. Using in vivo murine models, we also provide evidence of GLI-mediated regulation of the TP63 pathway. p63 expression appears essential to establish an optimally functioning HH pathway. These observations present a regulatory mechanism by which SUFU acts as an interacting node between the HH and TP63 pathways to mediate differentiation and maintain epidermal homeostasis. Disruption of this regulatory node can be an important contributor to multistep carcinogenesis.

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Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

Cited by 76 publications

References 52 publications

Morphogens and the Control of Cell Proliferation and Patterning in the Spinal Cord

Morphogens and the Control of Cell Proliferation and Patterning in the Spinal Cord

Sox10 directs neural stem cells toward the oligodendrocyte lineage by decreasing Suppressor of Fused expression

Interaction between the TP63 and SHH pathways is an important determinant of epidermal homeostasis

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