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Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis.

Publication ,  Journal Article
Madan, B; Harmston, N; Nallan, G; Montoya, A; Faull, P; Petretto, E; Virshup, DM
Published in: J Clin Invest
December 3, 2018

Activating mutations in the Wnt pathway drive a variety of cancers, but the specific targets and pathways activated by Wnt ligands are not fully understood. To bridge this knowledge gap, we performed a comprehensive time-course analysis of Wnt-dependent signaling pathways in an orthotopic model of Wnt-addicted pancreatic cancer, using a porcupine (PORCN) inhibitor currently in clinical trials, and validated key results in additional Wnt-addicted models. The temporal analysis of the drug-perturbed transcriptome demonstrated direct and indirect regulation of more than 3,500 Wnt-activated genes (23% of the transcriptome). Regulation was both via Wnt/β-catenin and through the modulation of protein abundance of important transcription factors, including MYC, via Wnt-dependent stabilization of proteins (Wnt/STOP). Our study identifies a central role of Wnt/β-catenin and Wnt/STOP signaling in controlling ribosome biogenesis, a key driver of cancer proliferation.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

December 3, 2018

Volume

128

Issue

12

Start / End Page

5620 / 5633

Location

United States

Related Subject Headings

  • Wnt Signaling Pathway
  • Transcriptome
  • Ribosomes
  • Proto-Oncogene Proteins c-myc
  • Protein Stability
  • Pancreatic Neoplasms
  • Neoplasms, Experimental
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice
 

Citation

APA
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ICMJE
MLA
NLM
Madan, B., Harmston, N., Nallan, G., Montoya, A., Faull, P., Petretto, E., & Virshup, D. M. (2018). Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis. J Clin Invest, 128(12), 5620–5633. https://doi.org/10.1172/JCI122383
Madan, Babita, Nathan Harmston, Gahyathiri Nallan, Alex Montoya, Peter Faull, Enrico Petretto, and David M. Virshup. “Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis.J Clin Invest 128, no. 12 (December 3, 2018): 5620–33. https://doi.org/10.1172/JCI122383.
Madan B, Harmston N, Nallan G, Montoya A, Faull P, Petretto E, et al. Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis. J Clin Invest. 2018 Dec 3;128(12):5620–33.
Madan, Babita, et al. “Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis.J Clin Invest, vol. 128, no. 12, Dec. 2018, pp. 5620–33. Pubmed, doi:10.1172/JCI122383.
Madan B, Harmston N, Nallan G, Montoya A, Faull P, Petretto E, Virshup DM. Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis. J Clin Invest. 2018 Dec 3;128(12):5620–5633.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

December 3, 2018

Volume

128

Issue

12

Start / End Page

5620 / 5633

Location

United States

Related Subject Headings

  • Wnt Signaling Pathway
  • Transcriptome
  • Ribosomes
  • Proto-Oncogene Proteins c-myc
  • Protein Stability
  • Pancreatic Neoplasms
  • Neoplasms, Experimental
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice