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Article

Control of Expression of Key Cell Cycle Enzymes Drives Cell Line-Specific Functions of CDK7 in Human PDAC Cells

Institute of Molecular Tumor Biology, Faculty of Medicine, University Muenster, 48149 Muenster, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Atsushi Matsuzawa
Int. J. Mol. Sci. 2022, 23(2), 812; https://doi.org/10.3390/ijms23020812
Received: 26 November 2021 / Revised: 30 December 2021 / Accepted: 8 January 2022 / Published: 12 January 2022
(This article belongs to the Special Issue Kinase Signal Transduction 3.0)
Inhibition of the dual function cell cycle and transcription kinase CDK7 is known to affect the viability of cancer cells, but the mechanisms underlying cell line-specific growth control remain poorly understood. Here, we employed a previously developed, highly specific small molecule inhibitor that non-covalently blocks ATP binding to CDK7 (LDC4297) to study the mechanisms underlying cell line-specific growth using a panel of genetically heterogeneous human pancreatic tumor lines as model system. Although LDC4297 diminished both transcription rates and CDK T-loop phosphorylation in a comparable manner, some PDAC lines displayed significantly higher sensitivity than others. We focused our analyses on two well-responsive lines (Mia-Paca2 and Panc89) that, however, showed significant differences in their viability upon extended exposure to limiting LDC4297 concentrations. Biochemical and RNAseq analysis revealed striking differences in gene expression and cell cycle control. Especially the downregulation of a group of cell cycle control genes, among them CDK1/2 and CDC25A/C, correlated well to the observed viability differences in Panc89 versus Mia-Paca2 cells. A parallel downregulation of regulatory pathways supported the hypothesis of a feedforward programmatic effect of CDK7 inhibitors, eventually causing hypersensitivity of PDAC lines. View Full-Text
Keywords: cyclin-dependent kinase 7/CDK7; pancreatic cancer; non-covalent CDK7 inhibitor cyclin-dependent kinase 7/CDK7; pancreatic cancer; non-covalent CDK7 inhibitor
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MDPI and ACS Style

Kolloch, L.; Kreinest, T.; Meisterernst, M.; Oeckinghaus, A. Control of Expression of Key Cell Cycle Enzymes Drives Cell Line-Specific Functions of CDK7 in Human PDAC Cells. Int. J. Mol. Sci. 2022, 23, 812. https://doi.org/10.3390/ijms23020812

AMA Style

Kolloch L, Kreinest T, Meisterernst M, Oeckinghaus A. Control of Expression of Key Cell Cycle Enzymes Drives Cell Line-Specific Functions of CDK7 in Human PDAC Cells. International Journal of Molecular Sciences. 2022; 23(2):812. https://doi.org/10.3390/ijms23020812

Chicago/Turabian Style

Kolloch, Lina, Teresa Kreinest, Michael Meisterernst, and Andrea Oeckinghaus. 2022. "Control of Expression of Key Cell Cycle Enzymes Drives Cell Line-Specific Functions of CDK7 in Human PDAC Cells" International Journal of Molecular Sciences 23, no. 2: 812. https://doi.org/10.3390/ijms23020812

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