Abstract
Nuclear factor kappa B (NF-κB)-mediated transcription is an important mediator for cellular responses to DNA damage. Genotoxic agents trigger a 'nuclear-to-cytoplasmic' NF-κB activation signaling pathway; however, the early nuclear signaling cascade linking DNA damage and NF-κB activation is poorly understood. Here we report that Src-associated-substrate-during-mitosis-of-68kDa/KH domain containing, RNA binding, signal transduction associated 1 (Sam68/KHDRBS1) is a key NF-κB regulator in genotoxic stress-initiated signaling pathway. Sam68 deficiency abolishes DNA damage-stimulated polymers of ADP-ribose (PAR) production and the PAR-dependent NF-κB transactivation of anti-apoptotic genes. Sam68 deleted cells are hypersensitive to genotoxicity caused by DNA damaging agents. Upregulated Sam68 coincides with elevated PAR production and NF-κB-mediated anti-apoptotic transcription in human and mouse colon cancer. Knockdown of Sam68 sensitizes human colon cancer cells to genotoxic stress-induced apoptosis and genetic deletion of Sam68 dampens colon tumor burden in mice. Together our data reveal a novel function of Sam68 in the genotoxic stress-initiated nuclear signaling, which is crucial for colon tumorigenesis.
Keywords:
DNA damage responses; KHDRBS1; NF-kB; Sam68; cancer biology; colon cancer; human; mouse; signal transduction.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Adenoma / genetics*
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Adenoma / metabolism
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Adenoma / pathology
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Adenosine Diphosphate Ribose / metabolism
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Animals
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Carcinogenesis / genetics*
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Cell Line, Tumor
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Colon / metabolism
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Colon / pathology
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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DNA Damage
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Gene Expression Regulation, Neoplastic*
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Humans
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Mice
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Mice, Knockout
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NF-kappa B / genetics*
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NF-kappa B / metabolism
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Neoplasm Transplantation
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Poly (ADP-Ribose) Polymerase-1 / genetics
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Poly (ADP-Ribose) Polymerase-1 / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / genetics*
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RNA-Binding Proteins / metabolism
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Signal Transduction
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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KHDRBS1 protein, human
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NF-kappa B
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RNA, Small Interfering
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RNA-Binding Proteins
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Adenosine Diphosphate Ribose
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Parp1 protein, mouse
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Poly (ADP-Ribose) Polymerase-1