title: Mutant p53 cooperates with ETS2 to promote etoposide resistance.
abstract: Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable" component of mtp53's gain-of-function activity.
authors.affiliation: Department of Biochemistry, University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Phi M
authors.initials: PM
authors.lastname: Do
authors.forename: Lakshman
authors.initials: L
authors.lastname: Varanasi
authors.forename: Songqing
authors.initials: S
authors.lastname: Fan
authors.forename: Chunyang
authors.initials: C
authors.lastname: Li
authors.forename: Iwona
authors.initials: I
authors.lastname: Kubacka
authors.forename: Virginia
authors.initials: V
authors.lastname: Newman
authors.forename: Krishna
authors.initials: K
authors.lastname: Chauhan
authors.forename: Silvano Rakeem
authors.initials: SR
authors.lastname: Daniels
authors.forename: Maurizio
authors.initials: M
authors.lastname: Boccetta
authors.forename: Michael R
authors.initials: MR
authors.lastname: Garrett
authors.forename: Runzhao
authors.initials: R
authors.lastname: Li
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C494069:ETS2 protein, human; D009687:Nuclear Proteins; D050787:Proto-Oncogene Protein c-ets-2; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D010727:Phosphoric Diester Hydrolases; C474866:TDP2 protein, human