The PI3 kinase-Akt pathway mediates Wnt3a-induced proliferation

Kim, Sung‐Eun; Lee, Won Jeong; Choi, Kang Yell

doi:10.1016/j.cellsig.2006.08.008

Cited by 66 publications

(48 citation statements)

References 44 publications

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“…The dephosphorylated (active) form of GSK3β promotes β-catenin degradation by phosphorylating β-catenin on Ser33/37. 22,23 Consistent with the known activation of β-catenin in AML blasts, 27,32 we found that the levels of nuclear β-catenin were elevated in blasts of a selected AML patient ( Figure 5A). We, therefore, analyzed whether NAMPT or SIRT2 inhibition resulted in increased phosphorylation of β-catenin.…”

Section: Inhibition Of Nampt or Sirtuin 2 Is Associated With β-Catenisupporting

confidence: 65%

“…[21][22] GSK3β is a member of the β-catenin degradation complex (by phosphorylation of β-catenin) consisting of axin, adenomatous polyposis coli (APC) and GSK3β. 22,23 In the absence of active GSK3β, β-catenin is activated and migrates into the nucleus, where it induces transcription of target genes by associating with LEF-1/TCF transcription factors. 24 Active nuclear β-catenin has been detected in blasts of myeloid leukemia patients as well as in patients with other hematologic malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…GSK3β targets the proto-oncogene β-catenin and promotes its ubiquitination and proteasomemediated degradation. 22,23 Inactivation of GSK3β leads to β-catenin accumulation and redistribution to the nucleus. 22,23 Nuclear β-catenin interacts with LEF-1/TCF transcription factors, which regulate cell survival and proliferation by activation of target genes c-myc, survivin and cyclin D1.…”

Section: Introductionmentioning

confidence: 99%

“…22,23 Inactivation of GSK3β leads to β-catenin accumulation and redistribution to the nucleus. 22,23 Nuclear β-catenin interacts with LEF-1/TCF transcription factors, which regulate cell survival and proliferation by activation of target genes c-myc, survivin and cyclin D1. 24 β-catenin induces proliferation and survival, but inhibits differentiation of hematopoietic stem cells (HSC).…”

Section: Introductionmentioning

confidence: 99%

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The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

Liu¹,

Klimenkova²,

Klimiankou³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundInhibitors of nicotinamide phosphoribosyltransferase have recently been validated as therapeutic targets in leukemia, but the mechanism of leukemogenic transformation downstream of this enzyme is unclear. Design and MethodsHere, we evaluated whether nicotinamide phosphoribosyltransferase's effects on aberrant proliferation and survival of myeloid leukemic cells are dependent on sirtuin and delineated the downstream signaling pathways operating during this process. ResultsWe identified significant upregulation of sirtuin 2 and nicotinamide phosphoribosyltransferase levels in primary acute myeloid leukemia blasts compared to in hematopoietic progenitor cells from healthy individuals. Importantly, specific inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 significantly reduced proliferation and induced apoptosis in human acute myeloid leukemia cell lines and primary blasts. Intriguingly, we found that protein kinase B/AKT could be deacetylated by nicotinamide phosphoribosyltransferase and sirtuin 2. The anti-leukemic effects of the inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 were accompanied by acetylation of protein kinase B/AKT with subsequent inhibition by dephosphorylation. This leads to activation of glycogen synthase kinase-3 β via diminished phosphorylation and, ultimately, inactivation of β-catenin by phosphorylation. ConclusionsOur results provide strong evidence that nicotinamide phosphoribosyltransferase and sirtuin 2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the protein kinase B/AKT/ glycogen synthase kinase-3 β/β-catenin pathway is a target for inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 and, thereby, leukemia cell proliferation.

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Section: Inhibition Of Nampt or Sirtuin 2 Is Associated With β-Catenisupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

Liu¹,

Klimenkova²,

Klimiankou³

et al. 2011

Haematologica

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“…Activation of Akt-signaling is involved in Wnt3a-induced proliferation of fibroblasts. 143 GSK3b that plays a major role within the Wnt pathway is a target of the phosphatidylinositol 3-kinase(PI3K)/Akt cascade, which is also activated in most AML cases. On the one hand, Aktdependent phosphorylation of GSK3b leading to its inactivation might be triggered by FLT3-ITD mutations as described above.…”

Section: Other Mechanisms Of Aberrant Wnt Signaling In Amlmentioning

confidence: 99%

The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia

Steffen

Berdel

et al. 2007

Leukemia

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Wnt signaling plays an important role in stem cell self-renewal and proliferation. Aberrant activation of Wnt signaling and its downstream targets are intimately linked with several types of cancer with colon cancer being the best-studied example. However, recent results also suggest an important role of Wnt signaling in normal as well as leukemic hematopoietic stem cells. Aberrant activation of Wnt signaling and downstream effectors has been demonstrated in acute myeloid leukemia. Here, mutant receptor tyrosine kinases, such as Flt3 and chimeric transcription factors such as promyelocytic leukemia-retinoic acid receptor-a and acute myeloid leukemia1-ETO, induce downstream Wnt signaling events. These findings suggest that the Wnt signaling pathway is an important target in several leukemogenic pathways and may provide a novel opportunity for targeting leukemic stem cells.

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Translational embryology: Using embryonic principles to generate pancreatic endocrine cells from embryonic stem cells

Spence

Wells

2007

Developmental Dynamics

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Diseases that affect endodermally derived organs such as the lungs, liver, and pancreas include cystic fibrosis, chronic hepatitis, and diabetes, respectively. Despite the prevalence of these diseases, cures remain elusive. While several promising transplantation-based therapies exist for some diseases such as Type 1 diabetes, they are currently limited by the availability of donor-derived tissues. Embryonic stem cells are a promising and renewable source of tissue for transplantation; however, directing their differentiation into specific, adult cell lineages remains a significant challenge. In this review, we will focus on one endodermally derived organ, the pancreas, and discuss how studies of embryonic pancreas development have been used as the basis for the directed, step-wise differentiation of mouse and human embryonic stem cells into pancreatic endocrine cells that are capable of rescuing Type 1 diabetes in animal models.

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The PI3 kinase-Akt pathway mediates Wnt3a-induced proliferation

Cited by 66 publications

References 44 publications

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia

Translational embryology: Using embryonic principles to generate pancreatic endocrine cells from embryonic stem cells

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