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Wnt/Catenin Signaling in Adult Stem Cell Physiology and Disease

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Abstract

Wnt signaling plays an important role in development and disease. In this review we focus on the role of the canonical Wnt signaling pathway in somatic stem cell biology and its critical role in tissue homeostasis. We present current knowledge how Wnt/β-catenin signaling affects tissue stem cell behavior in various organ systems, including the gut, mammary gland, the hematopoietic and nervous system. We discuss evidence that canonical Wnt signaling can both maintain potency and an undifferentiated state as well as cause differentiation in somatic stem cells, depending on the cellular and environmental context. Based on studies by our lab and others, we will attempt to explain the dichotomous behavior of this signaling pathway in determining cell fate decisions and put special emphasis on the interaction of β-catenin with two highly homologous co-activator proteins, CBP and p300, to shed light on the their differential role in the outcome of Wnt/β-catenin signaling. Furthermore, we review current knowledge regarding the aberrant regulation of Wnt/β-catenin signaling in cancer biology, particularly its pivotal role in the context of cancer stem cells. Finally, we discuss data demonstrating that small molecule modulators of the β-catenin/co-activator interaction can be used to shift the balance between undifferentiated proliferation and differentiation, which potentially presents a promising therapeutic approach to stem cell based disease mechanisms.

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Abbreviations

CSC:

Cancer stem cell

LSC:

Leukemic stem cell

TIC:

Tumor initiating cell

EMT:

Epithelial-mesenchymal transition

SSC:

Somatic stem cell

CBP:

CREB-binding protein

p300:

E1A binding protein p300

TCF:

T-cell factor

LEF:

Lymphoid enhancer factor

Fzd:

Frizzled

APC:

Adenomatous polyposis coli

GSK-3β:

Glycogen synthase kinase 3

CNS:

Central nervous system

Lrp:

Low-density lipoprotein receptor-related protein

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Acknowledgments

MK gratefully acknowledges support from USC Norris Comprehensive Cancer Center Support Grant P30 CA014089, NIH 1R01CA166161-01A1 and NIH 1R01 HL112638-01.

YMK gratefully acknowledges support from NIH Grant R01CA172896.

AR gratefully acknowledges support from the California Institute for Regenerative Medicine (CIRM) clinical fellowship TG2-01161.

Disclosure

Michael Kahn is a consultant and equity holder in Prism Pharmaceuticals.

The remaining authors indicate no potential conflicts of interest.

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Ring, A., Kim, YM. & Kahn, M. Wnt/Catenin Signaling in Adult Stem Cell Physiology and Disease. Stem Cell Rev and Rep 10, 512–525 (2014). https://doi.org/10.1007/s12015-014-9515-2

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