ERK-mediated TIMELESS expression suppresses G2/M arrest in colon cancer cells
| Autor: | Jamie L. McCall, Beth K. Neilsen, Robert E. Lewis, Danielle E. Frodyma, Kurt W. Fisher |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cell Cell Cycle Proteins Biochemistry Histones 0302 clinical medicine Medicine and Health Sciences Small interfering RNAs Cell Cycle and Cell Division RNA Small Interfering Post-Translational Modification Phosphorylation Multidisciplinary Intracellular Signaling Peptides and Proteins Nuclear Proteins Cell cycle Protein-Tyrosine Kinases G2 Phase Cell Cycle Checkpoints Gene Expression Regulation Neoplastic Nucleic acids Wee1 Circadian Rhythms medicine.anatomical_structure Oncology Cell Processes 030220 oncology & carcinogenesis Colonic Neoplasms Medicine Research Article Cell Physiology Timeless MAP Kinase Signaling System Science Biology 03 medical and health sciences Cell Line Tumor CDC2 Protein Kinase medicine Genetics Humans Non-coding RNA Cell Proliferation Colorectal Cancer Cyclin-dependent kinase 1 Cell growth Cancers and Neoplasms Biology and Life Sciences Proteins Cell Biology DNA HCT116 Cells Cell Metabolism Gene regulation 030104 developmental biology Cancer cell Checkpoint Kinase 1 Cancer research biology.protein DNA damage RNA Gene expression Chronobiology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 1, p e0209224 (2019) |
| ISSN: | 1932-6203 |
| Popis: | The cell cycle is under circadian regulation. Oncogenes can dysregulate circadian-regulated genes to disrupt the cell cycle, promoting tumor cell proliferation. As a regulator of G2/M arrest in response to DNA damage, the circadian gene Timeless Circadian Clock (TIMELESS) coordinates this connection and is a potential locus for oncogenic manipulation. TIMELESS expression was evaluated using RNASeq data from TCGA and by RT-qPCR and western blot analysis in a panel of colon cancer cell lines. TIMELESS expression following ERK inhibition was examined via western blot. Cell metabolic capacity, propidium iodide, and CFSE staining were used to evaluate the effect of TIMELESS depletion on colon cancer cell survival and proliferation. Cell metabolic capacity following TIMELESS depletion in combination with Wee1 or CHK1 inhibition was assessed. TIMELESS is overexpressed in cancer and required for increased cancer cell proliferation. ERK activation promotes TIMELESS expression. TIMELESS depletion increases γH2AX, a marker of DNA damage, and triggers G2/M arrest via increased CHK1 and CDK1 phosphorylation. TIMELESS depletion in combination with Wee1 or CHK1 inhibition causes an additive decrease in cancer cell metabolic capacity with limited effects in non-transformed human colon epithelial cells. The data show that ERK activation contributes to the overexpression of TIMELESS in cancer. Depletion of TIMELESS increases γH2AX and causes G2/M arrest, limiting cell proliferation. These results demonstrate a role for TIMELESS in cancer and encourage further examination of the link between circadian rhythm dysregulation and cancer cell proliferation. |
| Databáze: | OpenAIRE |
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