LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest.
Inactivating mutations in the serine-threonine kinase LKB1 (STK11) are found in most patients with Peutz-Jeghers syndrome; however the function of LKB1 is unknown. We found that LKB1 binds to and regulates brahma-related gene 1 (Brg1), an essential component of chromatin remodeling complexes. The association requires the N terminus of LKB1 and the helicase domain of Brg1 and LKB1 stimulates the ATPase activity of Brg1. Brg1 expression in SW13 cells induces the formation of flat cells indicative of cell cycle arrest and senescence. Expression of a kinase-dead mutant of LKB1, SL26, in SW13 cells blocks the formation of Brg1-induced flat cells, indicating that LKB1 is required for Brg1-dependent growth arrest. The inability of mutants of LKB1 to mediate Brg1-dependent growth arrest may explain the manifestations of Peutz-Jeghers syndrome.
Marignani
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PA
Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. marignan@uhnres.utoronto.ca
Kanai
F
F
Carpenter
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CL
D000091162:AMP-Activated Protein Kinase Kinases; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D003001:Cloning, Molecular; D004265:DNA Helicases / Q000737:chemistry / Q000378:metabolism; D015723:Gene Library; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010580:Peutz-Jeghers Syndrome / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D009687:Nuclear Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D000251:Adenosine Triphosphatases; C084108:SMARCA4 protein, human; D004265:DNA Helicases