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Article ; Online: Restoring two tumor suppressor pathways with one PAWI.

Myers, Rebecca L / Klein, Peter S

Cell chemical biology

2021 Volume 28, Issue 5, Page(s) 590–593

Abstract: In this issue of Cell Chemical Biology, Cheng et al. (2021) identify a class of drugs that activate a mitotic stress-dependent signaling cascade, which culminates in p53 activation and Wnt pathway inhibition (PAWI). PAWI compounds may therefore be ... ...

Abstract	In this issue of Cell Chemical Biology, Cheng et al. (2021) identify a class of drugs that activate a mitotic stress-dependent signaling cascade, which culminates in p53 activation and Wnt pathway inhibition (PAWI). PAWI compounds may therefore be effective in cancers associated with loss of p53 and activation of Wnt signaling.
MeSH term(s)	Humans ; Neoplasms/drug therapy ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Wnt Signaling Pathway
Chemical Substances	Tumor Suppressor Protein p53
Language	English
Publishing date	2021-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2021.04.017
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Article ; Online: Leukemic Stem Cell Culture in Cytokine-Free Medium.

Liu, Xiaolei / Klein, Peter S

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2185, Page(s) 259–265

Abstract: Leukemia-initiating cells, also known as leukemic stem cells (LSCs), are experimentally defined by their ability to engraft immunocompromised mice and are believed to be a major cause of relapse in acute myeloid leukemia (AML). Despite the aggressive ... ...

Abstract	Leukemia-initiating cells, also known as leukemic stem cells (LSCs), are experimentally defined by their ability to engraft immunocompromised mice and are believed to be a major cause of relapse in acute myeloid leukemia (AML). Despite the aggressive characteristics of acute leukemia, AML blasts are difficult to culture once removed from the patient, and LSCs, which are a minor fraction of the blast population, are especially difficult to transplant after culture. This impedes development of new therapies for AML that target LSCs. Here, we present a simple strategy to culture LSCs in cytokine-free medium and to perform flow cytometric analysis of the resulting cell population for the characterization of LSCs maintenance and differentiation.
MeSH term(s)	Cell Culture Techniques ; Cytokines/pharmacology ; Humans ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Tumor Cells, Cultured
Chemical Substances	Cytokines
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-0810-4_15
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Article ; Online: When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex.

Li, Chenchen / Furth, Emma E / Rustgi, Anil K / Klein, Peter S

Cells

2023 Volume 12, Issue 18

Abstract: The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a "canonical" Wnt pathway that ... ...

Abstract	The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a "canonical" Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is β-catenin, which is stabilized by inhibition of GSK-3, allowing β-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of β-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers.
MeSH term(s)	Animals ; Wnt Signaling Pathway ; Glycogen Synthase Kinase 3 ; Axin Protein ; beta Catenin ; Adenomatous Polyposis Coli
Chemical Substances	Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Axin Protein ; beta Catenin
Language	English
Publishing date	2023-09-12
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12182256
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Article ; Online: Lithium and Therapeutic Targeting of GSK-3.

Snitow, Melinda E / Bhansali, Rahul S / Klein, Peter S

Cells

2021 Volume 10, Issue 2

Abstract: Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of ... ...

Abstract	Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections.
MeSH term(s)	Animals ; Antimanic Agents/pharmacology ; Antimanic Agents/therapeutic use ; Bipolar Disorder/drug therapy ; Bipolar Disorder/metabolism ; Coronavirus/drug effects ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Lithium Compounds/pharmacology ; Lithium Compounds/therapeutic use ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/metabolism ; Phosphoric Monoester Hydrolases/metabolism ; Severe Acute Respiratory Syndrome/drug therapy ; Severe Acute Respiratory Syndrome/metabolism ; Signal Transduction/drug effects
Chemical Substances	Antimanic Agents ; Lithium Compounds ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2)
Language	English
Publishing date	2021-01-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10020255
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Article ; Online: Glycogen synthase kinase-3 and alternative splicing.

Liu, Xiaolei / Klein, Peter S

Wiley interdisciplinary reviews. RNA

2018 Volume 9, Issue 6, Page(s) e1501

Abstract: Glycogen synthase kinase-3 (GSK-3) is a highly conserved negative regulator of receptor tyrosine kinase, cytokine, and Wnt signaling pathways. Stimulation of these pathways inhibits GSK-3 to modulate diverse downstream effectors that include ... ...

Abstract	Glycogen synthase kinase-3 (GSK-3) is a highly conserved negative regulator of receptor tyrosine kinase, cytokine, and Wnt signaling pathways. Stimulation of these pathways inhibits GSK-3 to modulate diverse downstream effectors that include transcription factors, nutrient sensors, glycogen synthesis, mitochondrial function, circadian rhythm, and cell fate. GSK-3 also regulates alternative splicing in response to T-cell receptor activation, and recent phosphoproteomic studies have revealed that multiple splicing factors and regulators of RNA biosynthesis are phosphorylated in a GSK-3-dependent manner. Furthermore, inhibition of GSK-3 alters the splicing of hundreds of mRNAs, indicating a broad role for GSK-3 in the regulation of RNA processing. GSK-3-regulated phosphoproteins include SF3B1, SRSF2, PSF, RBM8A, nucleophosmin 1 (NPM1), and PHF6, many of which are mutated in leukemia and myelodysplasia. As GSK-3 is inhibited by pathways that are pathologically activated in leukemia and loss of Gsk3 in hematopoietic cells causes a severe myelodysplastic neoplasm in mice, these findings strongly implicate GSK-3 as a critical regulator of mRNA processing in normal and malignant hematopoiesis. This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
MeSH term(s)	Alternative Splicing ; Animals ; Glycogen Synthase Kinase 3/genetics ; Humans ; Mutation ; Neoplasms/genetics
Chemical Substances	Glycogen Synthase Kinase 3 (EC 2.7.11.26)
Language	English
Publishing date	2018-08-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2634714-3
ISSN	1757-7012 ; 1757-7004
ISSN (online)	1757-7012
ISSN	1757-7004
DOI	10.1002/wrna.1501
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Article: Wnt Signaling in Normal and Malignant Stem Cells.

Bhavanasi, Dheeraj / Klein, Peter S

Current stem cell reports

2016 Volume 2, Issue 4, Page(s) 379–387

Abstract: Wnt signaling plays important roles in stem cell self-renewal and differentiation in adults as well as in embryonic development. Mutations that activate canonical Wnt/β-catenin signaling also initiate and maintain several cancer states, including ... ...

Abstract	Wnt signaling plays important roles in stem cell self-renewal and differentiation in adults as well as in embryonic development. Mutations that activate canonical Wnt/β-catenin signaling also initiate and maintain several cancer states, including colorectal cancer and leukemia, and hence Wnt inhibitors are currently being explored as therapeutic options. In this review, we summarize previous studies and update recent findings on canonical Wnt signaling and its components, as well as their roles in somatic stem cell homeostasis and maintenance of cancer initiating cells.
Language	English
Publishing date	2016-10-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2808623-5
ISSN	2198-7866
ISSN	2198-7866
DOI	10.1007/s40778-016-0068-y
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Article ; Online: Chromatin accessibility and histone acetylation in the regulation of competence in early development.

Esmaeili, Melody / Blythe, Shelby A / Tobias, John W / Zhang, Kai / Yang, Jing / Klein, Peter S

Developmental biology

2020 Volume 462, Issue 1, Page(s) 20–35

Abstract: As development proceeds, inductive cues are interpreted by competent tissues in a spatially and temporally restricted manner. While key inductive signaling pathways within competent cells are well-described at a molecular level, the mechanisms by which ... ...

Abstract	As development proceeds, inductive cues are interpreted by competent tissues in a spatially and temporally restricted manner. While key inductive signaling pathways within competent cells are well-described at a molecular level, the mechanisms by which tissues lose responsiveness to inductive signals are not well understood. Localized activation of Wnt signaling before zygotic gene activation in Xenopus laevis leads to dorsal development, but competence to induce dorsal genes in response to Wnts is lost by the late blastula stage. We hypothesize that loss of competence is mediated by changes in histone modifications leading to a loss of chromatin accessibility at the promoters of Wnt target genes. We use ATAC-seq to evaluate genome-wide changes in chromatin accessibility across several developmental stages. Based on overlap with p300 binding, we identify thousands of putative cis-regulatory elements at the gastrula stage, including sites that lose accessibility by the end of gastrulation and are enriched for pluripotency factor binding motifs. Dorsal Wnt target gene promoters are not accessible after the loss of competence in the early gastrula while genes involved in mesoderm and neural crest development maintain accessibility at their promoters. Inhibition of histone deacetylases increases acetylation at the promoters of dorsal Wnt target genes and extends competence for dorsal gene induction by Wnt signaling. Histone deacetylase inhibition, however, is not sufficient to extend competence for mesoderm or neural crest induction. These data suggest that chromatin state regulates the loss of competence to inductive signals in a context-dependent manner.
MeSH term(s)	Acetylation ; Animals ; Blastula/metabolism ; Chromatin/genetics ; Chromatin/metabolism ; Embryonic Induction/genetics ; Gastrula/metabolism ; Gastrulation/genetics ; Gene Expression Regulation, Developmental/genetics ; Histones/genetics ; Histones/metabolism ; Mesoderm/metabolism ; Neural Crest/metabolism ; Signal Transduction ; Transcription Factors/metabolism ; Wnt Proteins/metabolism ; Wnt Signaling Pathway/genetics ; Wnt Signaling Pathway/physiology ; Xenopus Proteins/metabolism ; Xenopus laevis/embryology ; Xenopus laevis/metabolism
Chemical Substances	Chromatin ; Histones ; Transcription Factors ; Wnt Proteins ; Xenopus Proteins
Language	English
Publishing date	2020-02-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2020.02.013
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Article: Expansion of human hematopoietic stem cells by inhibiting translation.

Li, Chenchen / Shin, Hanna / Bhavanasi, Dheeraj / Liu, Mai / Yu, Xiang / Peslak, Scott A / Liu, Xiaolei / Alvarez-Dominguez, Juan R / Blobel, Gerd A / Gregory, Brian D / Huang, Jian / Klein, Peter S

bioRxiv : the preprint server for biology

2023

Abstract: Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is ... ...

Abstract	Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is also a major obstacle to gene editing for inherited blood disorders. HSCs require a low rate of translation to maintain their capacity for self-renewal, but hematopoietic cytokines used to expand HSCs stimulate protein synthesis and impair long-term self-renewal. We previously described cytokine-free conditions that maintain but do not expand human and mouse HSCs ex vivo. Here we performed a high throughput screen and identified translation inhibitors that allow ex vivo expansion of human HSCs while minimizing cytokine exposure. Transplantation assays show a ~5-fold expansion of long-term HSCs from UCB after one week of culture in low cytokine conditions. Single cell transcriptomic analysis demonstrates maintenance of HSCs expressing mediators of the unfolded protein stress response, further supporting the importance of regulated proteostasis in HSC maintenance and expansion. This expansion method maintains and expands human HSCs after CRISPR/Cas9 editing of the
Language	English
Publishing date	2023-11-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.28.568925
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Article ; Online: The Tumor Suppressor

Liu, Xiaolei / Jones, William D / Quesnel-Vallières, Mathieu / Devadiga, Sudhish A / Lorent, Kristin / Valvezan, Alexander J / Myers, Rebecca L / Li, Ning / Lengner, Christopher J / Barash, Yoseph / Pack, Michael / Klein, Peter S

Journal of developmental biology

2023 Volume 11, Issue 3

Abstract: Neural crest (NC) is a unique vertebrate cell type arising from the border of the neural plate and epidermis that gives rise to diverse tissues along the entire body axis. Roberto Mayor and colleagues have made major contributions to our understanding of ...

Abstract	Neural crest (NC) is a unique vertebrate cell type arising from the border of the neural plate and epidermis that gives rise to diverse tissues along the entire body axis. Roberto Mayor and colleagues have made major contributions to our understanding of NC induction, delamination, and migration. We report that a truncating mutation of the classical tumor suppressor
Language	English
Publishing date	2023-06-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720870-9
ISSN	2221-3759 ; 2221-3759
ISSN (online)	2221-3759
ISSN	2221-3759
DOI	10.3390/jdb11030029
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Article ; Online: Autophagy is a signature of a signaling network that maintains hematopoietic stem cells.

Nguyen-McCarty, Michelle / Klein, Peter S

PloS one

2017 Volume 12, Issue 5, Page(s) e0177054

Abstract: Hematopoietic stem cells (HSCs) are able to self-renew and to differentiate into all blood cells. HSCs reside in a low-perfusion niche and depend on local signals to survive and to maintain the capacity for self-renewal. HSCs removed from the niche are ... ...

Abstract	Hematopoietic stem cells (HSCs) are able to self-renew and to differentiate into all blood cells. HSCs reside in a low-perfusion niche and depend on local signals to survive and to maintain the capacity for self-renewal. HSCs removed from the niche are unable to survive without addition of hematopoietic cytokines and rapidly lose their ability to self-renew. We reported previously that inhibition of both GSK-3 and mTORC1 is essential to maintain long-term HSCs ex vivo. Although Wnt/β-catenin signaling downstream of GSK-3 is required for this response, the downstream effectors of mTORC1 remain undefined. We now report that HSCs express a pro-autophagic gene signature and accumulate LC3 puncta only when both mTORC1 and GSK-3 are inhibited, identifying autophagy as a signature for a signaling network that maintains HSCs ex vivo. In addition, these conditions sustain HSC repopulating function despite an increased rate of global translation. Together, these findings provide new insight into the relative contributions of various mTORC1 outputs toward the maintenance of HSC function and build upon the growing body of literature implicating autophagy and tightly controlled protein synthesis as important modulators of diverse stem cell populations.
MeSH term(s)	Autophagy ; Hematopoietic Stem Cells/metabolism ; Humans ; Signal Transduction
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0177054
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