Abstract
In normal cells, p53 is activated by DNA damage checkpoint kinases to simultaneously control the G1/S and G2/M cell cycle checkpoints through transcriptional induction of p21(cip1) and Gadd45α. In p53-mutant tumors, cell cycle checkpoints are rewired, leading to dependency on the p38/MK2 pathway to survive DNA-damaging chemotherapy. Here we show that the RNA binding protein hnRNPA0 is the "successor" to p53 for checkpoint control. Like p53, hnRNPA0 is activated by a checkpoint kinase (MK2) and simultaneously controls both cell cycle checkpoints through distinct target mRNAs, but unlike p53, this is through the post-transcriptional stabilization of p27(Kip1) and Gadd45α mRNAs. This pathway drives cisplatin resistance in lung cancer, demonstrating the importance of post-transcriptional RNA control to chemotherapy response.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Animals
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Antineoplastic Agents / therapeutic use
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Cell Cycle Checkpoints / genetics*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cisplatin / therapeutic use
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Drug Resistance, Neoplasm / genetics*
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Female
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Gene Expression Regulation, Neoplastic
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Genetic Pleiotropy
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HEK293 Cells
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Heterogeneous-Nuclear Ribonucleoproteins / genetics*
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Heterogeneous-Nuclear Ribonucleoproteins / metabolism
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Humans
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Male
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Mice, Inbred C57BL
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Middle Aged
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Mutation*
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Neoplasms / drug therapy
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Neoplasms / genetics*
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Neoplasms / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Survival Analysis
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Tumor Suppressor Protein p53 / genetics*
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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GADD45A protein, human
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HNRNPA0 protein, human
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Heterogeneous-Nuclear Ribonucleoproteins
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Nuclear Proteins
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Tumor Suppressor Protein p53
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Cyclin-Dependent Kinase Inhibitor p27
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Cisplatin