Bayesian Network Inference Modeling Identifies TRIB1 as a Novel Regulator of Cell-Cycle Progression and Survival in Cancer Cells.

Abstract

Molecular networks governing responses to targeted therapies in cancer cells are complex dynamic systems that demonstrate nonintuitive behaviors. We applied a novel computational strategy to infer probabilistic causal relationships between network components based on gene expression. We constructed a model comprised of an ensemble of networks using multidimensional data from cell line models of cell-cycle arrest caused by inhibition of MEK1/2. Through simulation of a reverse-engineered Bayesian network model, we generated predictions of G1-S transition. The model identified known components of the cell-cycle machinery, such as CCND1, CCNE2, and CDC25A, as well as revealed novel regulators of G1-S transition, IER2, TRIB1, TRIM27. Experimental validation of model predictions confirmed 10 of 12 predicted genes to have a role in G1-S progression. Further analysis showed that TRIB1 regulated the cyclin D1 promoter via NFκB and AP-1 sites and sensitized cells to TRAIL-induced apoptosis. In clinical specimens of breast cancer, TRIB1 levels correlated with expression of NFκB and its target genes (IL8, CSF2), and TRIB1 copy number and expression were predictive of clinical outcome. Together, our results establish a critical role of TRIB1 in cell cycle and survival that is mediated via the modulation of NFκB signaling. Cancer Res; 77(7); 1575-85. ©2017 AACR.

• Authors: Rina Gendelman, Heming Xing, Olga K Mirzoeva, Preeti Sarde, Christina Curtis, Heidi S Feiler, Paul McDonagh, Joe W Gray, Iya Khalil, W Michael Korn
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 7 Pg. 1575-1585 (04 01 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28087598 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• CCND1 protein, human
• Intracellular Signaling Peptides and Proteins
• NF-kappa B
• TRIB1 protein, human
• Cyclin D1
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase Kinases

Topics

• Bayes Theorem
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Cycle
• Cell Line, Tumor
• Cell Survival
• Cyclin D1 (genetics)
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, physiology)
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• NF-kappa B (physiology)
• Phosphatidylinositol 3-Kinases (physiology)
• Promoter Regions, Genetic
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Signal Transduction (physiology)