Abstract
Activation of Crtc1 (also known as Mect1/Torc1) by a t(11;19) chromosomal rearrangement underlies the etiology of malignant salivary gland tumors. As LKB1 is a target for mutational inactivation in lung cancer and was recently shown to regulate hepatic Crtc2/CREB transcriptional activity in mice, we now present evidence suggesting disruption of an LKB1/Crtc pathway in cancer. Although Crtc1 is preferentially expressed in adult brain tissues, we observed elevated levels of steady-state Crtc1 in thoracic tumors. In addition, we show that somatic loss of LKB1 is associated with underphosphorylation of endogenous Crtc1, enhanced Crtc1 nuclear localization and enhanced expression of the Crtc prototypic target gene, NR4A2/Nurr1. Inhibition of NR4A2 was associated with growth suppression of LKB1 null tumors, but showed little effect on LKB1-wildtype cells. These data strengthen the role of dysregulated Crtc as a bona fide cancer gene, present a new element to the complex LKB1 tumorigenic axis, and suggest that Crtc genes may be aberrantly activated in a wider range of common adult malignancies.
MeSH terms
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AMP-Activated Protein Kinase Kinases
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Adult
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Brain / metabolism
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Cell Line, Tumor
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Cell Nucleus / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Fluorescent Antibody Technique
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Humans
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Immunoblotting
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Mutation*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Trans-Activators
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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CRTC1 protein, human
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DNA-Binding Proteins
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MAML2 protein, human
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NR4A2 protein, human
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Nuclear Proteins
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Nuclear Receptor Subfamily 4, Group A, Member 2
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Oncogene Proteins, Fusion
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Trans-Activators
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Transcription Factors
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Protein Serine-Threonine Kinases
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STK11 protein, human
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AMP-Activated Protein Kinase Kinases