ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.

Mayro, Benjamin

Hoj, Jacob P

Cerda-Smith, Christian G

Hutchinson, Haley M

Caminear, Michael W

Thrash, Hannah L

Winter, Peter S

Wardell, Suzanne E

McDonnell, Donald P

Wu, Colleen

Wood, Kris C

Pendergast, Ann Marie

2024-02-01T14:54:17Z

2024-02-01T14:54:17Z

2023-04

The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several oncogenic signals and cellular stressors. While the pathways controlling normoxic degradation of HIF-1α are well understood, the mechanisms supporting the sustained stabilization and activity of HIF-1α under Hx are less clear. We report that ABL kinase activity protects HIF-1α from proteasomal degradation during Hx. Using a fluorescence-activated cell sorting (FACS)-based CRISPR/Cas9 screen, we identified HIF-1α as a substrate of the cleavage and polyadenylation specificity factor-1 (CPSF1), an E3-ligase which targets HIF-1α for degradation in the presence of an ABL kinase inhibitor in Hx. We show that ABL kinases phosphorylate and interact with CUL4A, a cullin ring ligase adaptor, and compete with CPSF1 for CUL4A binding, leading to increased HIF-1α protein levels. Further, we identified the MYC proto-oncogene protein as a second CPSF1 substrate and show that active ABL kinase protects MYC from CPSF1-mediated degradation. These studies uncover a role for CPSF1 in cancer pathobiology as an E3-ligase antagonizing the expression of the oncogenic transcription factors, HIF-1α and MYC.

0027-8424

1091-6490

https://hdl.handle.net/10161/29974

eng

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences of the United States of America

10.1073/pnas.2210418120

https://creativecommons.org/licenses/by-nc/4.0

Humans

Ubiquitin-Protein Ligases

Cullin Proteins

Cleavage And Polyadenylation Specificity Factor

Proto-Oncogene Proteins c-myc

Transcription Factors

Gene Expression Regulation

Phosphorylation

Genes, abl

Hypoxia-Inducible Factor 1, alpha Subunit

Hypoxia

Protein Serine-Threonine Kinases

ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.

Journal article

Caminear, Michael W|0000-0002-8445-0927

Wardell, Suzanne E|0000-0002-5792-1447

McDonnell, Donald P|0000-0002-7331-4700

Wood, Kris C|0000-0002-5887-2253

e2210418120

16

Duke

School of Medicine

Student

Basic Science Departments

Clinical Science Departments

Institutes and Centers

Cell Biology

Pharmacology & Cancer Biology

Medicine

Orthopaedic Surgery

Medicine, Endocrinology, Metabolism, and Nutrition

Duke Cancer Institute

Institutes and Provost's Academic Units

Initiatives

Duke Innovation & Entrepreneurship

Regeneration Next Initiative

Published

120