The epithelial cell transforming sequence 2, a guanine nucleotide exchange factor for Rho GTPases, is repressed by p53 via protein methyltransferases and is required for G1-S transition.
The epithelial cell transforming sequence 2 (ECT2), a member of the Dbl family of guanine nucleotide exchange factor for Rho GTPases, is required for cytokinesis. The tumor suppressor p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest and apoptosis, in response to stress signals. Here, we showed that ECT2 is negatively regulated by wild-type p53 but not tumor-derived mutant p53 or other p53 family members. In addition, ECT2 is down-regulated in multiple cell lines by DNA damage agents and Nutlin-3, an MDM2 antagonist, in a p53-dependent manner. We also showed that the activity of the ECT2 promoter is repressed by wild-type p53, and to a lesser extent, by p21. In addition, the second activation domain in p53 is necessary for the efficient repression of ECT2. Importantly, we found that the ECT2 gene is bound by p53 in vivo in response to DNA damage and Nutlin-3 treatment. Furthermore, we provided evidence that inhibition of protein methyltransferases, especially arginine methyltransferases, relieve the repression of ECT2 induced by DNA damage or Nutlin-3 in a p53-dependent manner. Finally, we generated multiple cell lines in which ECT2 is inducibly knocked down and found that ECT2 knockdown triggers cell cycle arrest in G1. Taken together, we uncovered a novel function for ECT2 and provided a novel mechanism by which p53 represses gene expression via protein methyltransferases.
Scoumanne
Ariane
A
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Chen
Xinbin
X
D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D016193:G1 Phase / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016196:S Phase / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489850:ECT2 protein, human; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D008780:Methyltransferases; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases; D020741:rho GTP-Binding Proteins