Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness

Jiongjia Cheng; Masanao Tsuda; Karl Okolotowicz; Mary Dwyer; Paul J. Bushway; Alexandre R. Colas; Joseph J. Lancman; Dennis Schade; Isaac Perea-Gil; Arne A.N. Bruyneel; Jaechol Lee; Nirmal Vadgama; Justine Quach; Wesley L. McKeithan; Travis L. Biechele; Joseph C. Wu; Randall T. Moon; P. Duc Si Dong; Ioannis Karakikes; John R. Cashman; Mark Mercola

doi:10.1016/j.chembiol.2021.01.001

Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness

Jiongjia Cheng
, Masanao Tsuda
, Karl Okolotowicz
, Mary Dwyer
, Paul J. Bushway
, Alexandre R. Colas
, Joseph J. Lancman
, Dennis Schade
, Isaac Perea-Gil
, Arne A.N. Bruyneel
, Jaechol Lee
, Nirmal Vadgama
, Justine Quach
, Wesley L. McKeithan
, Travis L. Biechele
, Joseph C. Wu
, Randall T. Moon
, P. Duc Si Dong
, Ioannis Karakikes
, John R. Cashman

Mark Mercola

Human BioMolecular Research Institute
Sanford Burnham Prebys Medical Discovery Institute
University of California at San Diego
Kiel University
Stanford University
University of Washington

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Wnt signaling plays a central role in tissue maintenance and cancer. Wnt activates downstream genes through β-catenin, which interacts with TCF/LEF transcription factors. A major question is how this signaling is coordinated relative to tissue organization and renewal. We used a recently described class of small molecules that binds tubulin to reveal a molecular cascade linking stress signaling through ATM, HIPK2, and p53 to the regulation of TCF/LEF transcriptional activity. These data suggest a mechanism by which mitotic and genotoxic stress can indirectly modulate Wnt responsiveness to exert coherent control over cell shape and renewal. These findings have implications for understanding tissue morphogenesis and small-molecule anticancer therapeutics.

Original language	English
Pages (from-to)	625-635.e5
Journal	Cell Chemical Biology
Volume	28
Issue number	5
DOIs	https://doi.org/10.1016/j.chembiol.2021.01.001
State	Published - 20 May 2021
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Aurora kinases
LEF
TCF
Wnt
ataxia telangiectasia mutated/ATM
homeodomain-interacting protein kinase/HIPK2
p53
β-catenin

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10.1016/j.chembiol.2021.01.001

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Cheng, J., Tsuda, M., Okolotowicz, K., Dwyer, M., Bushway, P. J., Colas, A. R., Lancman, J. J., Schade, D., Perea-Gil, I., Bruyneel, A. A. N., Lee, J., Vadgama, N., Quach, J., McKeithan, W. L., Biechele, T. L., Wu, J. C., Moon, R. T., Si Dong, P. D., Karakikes, I., ... Mercola, M. (2021). Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness. Cell Chemical Biology, 28(5), 625-635.e5. https://doi.org/10.1016/j.chembiol.2021.01.001

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title = "Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness",

abstract = "Wnt signaling plays a central role in tissue maintenance and cancer. Wnt activates downstream genes through β-catenin, which interacts with TCF/LEF transcription factors. A major question is how this signaling is coordinated relative to tissue organization and renewal. We used a recently described class of small molecules that binds tubulin to reveal a molecular cascade linking stress signaling through ATM, HIPK2, and p53 to the regulation of TCF/LEF transcriptional activity. These data suggest a mechanism by which mitotic and genotoxic stress can indirectly modulate Wnt responsiveness to exert coherent control over cell shape and renewal. These findings have implications for understanding tissue morphogenesis and small-molecule anticancer therapeutics.",

keywords = "Aurora kinases, LEF, TCF, Wnt, ataxia telangiectasia mutated/ATM, homeodomain-interacting protein kinase/HIPK2, p53, β-catenin",

author = "Jiongjia Cheng and Masanao Tsuda and Karl Okolotowicz and Mary Dwyer and Bushway, \{Paul J.\} and Colas, \{Alexandre R.\} and Lancman, \{Joseph J.\} and Dennis Schade and Isaac Perea-Gil and Bruyneel, \{Arne A.N.\} and Jaechol Lee and Nirmal Vadgama and Justine Quach and McKeithan, \{Wesley L.\} and Biechele, \{Travis L.\} and Wu, \{Joseph C.\} and Moon, \{Randall T.\} and \{Si Dong\}, \{P. Duc\} and Ioannis Karakikes and Cashman, \{John R.\} and Mark Mercola",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

year = "2021",

month = may,

day = "20",

doi = "10.1016/j.chembiol.2021.01.001",

language = "English",

volume = "28",

pages = "625--635.e5",

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Cheng, J, Tsuda, M, Okolotowicz, K, Dwyer, M, Bushway, PJ, Colas, AR, Lancman, JJ, Schade, D, Perea-Gil, I, Bruyneel, AAN, Lee, J, Vadgama, N, Quach, J, McKeithan, WL, Biechele, TL, Wu, JC, Moon, RT, Si Dong, PD, Karakikes, I, Cashman, JR & Mercola, M 2021, 'Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness', Cell Chemical Biology, vol. 28, no. 5, pp. 625-635.e5. https://doi.org/10.1016/j.chembiol.2021.01.001

TY - JOUR

T1 - Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness

AU - Cheng, Jiongjia

AU - Tsuda, Masanao

AU - Okolotowicz, Karl

AU - Dwyer, Mary

AU - Bushway, Paul J.

AU - Colas, Alexandre R.

AU - Lancman, Joseph J.

AU - Schade, Dennis

AU - Perea-Gil, Isaac

AU - Bruyneel, Arne A.N.

AU - Lee, Jaechol

AU - Vadgama, Nirmal

AU - Quach, Justine

AU - McKeithan, Wesley L.

AU - Biechele, Travis L.

AU - Wu, Joseph C.

AU - Moon, Randall T.

AU - Si Dong, P. Duc

AU - Karakikes, Ioannis

AU - Cashman, John R.

AU - Mercola, Mark

PY - 2021/5/20

Y1 - 2021/5/20

N2 - Wnt signaling plays a central role in tissue maintenance and cancer. Wnt activates downstream genes through β-catenin, which interacts with TCF/LEF transcription factors. A major question is how this signaling is coordinated relative to tissue organization and renewal. We used a recently described class of small molecules that binds tubulin to reveal a molecular cascade linking stress signaling through ATM, HIPK2, and p53 to the regulation of TCF/LEF transcriptional activity. These data suggest a mechanism by which mitotic and genotoxic stress can indirectly modulate Wnt responsiveness to exert coherent control over cell shape and renewal. These findings have implications for understanding tissue morphogenesis and small-molecule anticancer therapeutics.

AB - Wnt signaling plays a central role in tissue maintenance and cancer. Wnt activates downstream genes through β-catenin, which interacts with TCF/LEF transcription factors. A major question is how this signaling is coordinated relative to tissue organization and renewal. We used a recently described class of small molecules that binds tubulin to reveal a molecular cascade linking stress signaling through ATM, HIPK2, and p53 to the regulation of TCF/LEF transcriptional activity. These data suggest a mechanism by which mitotic and genotoxic stress can indirectly modulate Wnt responsiveness to exert coherent control over cell shape and renewal. These findings have implications for understanding tissue morphogenesis and small-molecule anticancer therapeutics.

KW - Aurora kinases

KW - LEF

KW - TCF

KW - Wnt

KW - ataxia telangiectasia mutated/ATM

KW - homeodomain-interacting protein kinase/HIPK2

KW - p53

KW - β-catenin

UR - https://www.scopus.com/pages/publications/85100668491

U2 - 10.1016/j.chembiol.2021.01.001

DO - 10.1016/j.chembiol.2021.01.001

M3 - Article

C2 - 33503403

AN - SCOPUS:85100668491

SN - 2451-9456

VL - 28

SP - 625-635.e5

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 5

ER -

Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness

Abstract

UN SDGs

Keywords

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