title: Serine substitution of proline at codon 151 of TP53 confers gain of function activity leading to anoikis resistance and tumor progression of head and neck cancer cells.
abstract: OBJECTIVE
  Mutation of the TP53 gene occurs in more than half of cases of head and neck squamous cell carcinoma (HNSCC). However, little is known about how specific TP53 mutations affect tumor progression. The objective of this study is to determine the gain of function of mutant p53 with a proline-to-serine substitution at codon 151.
  
  
  METHODS
  Laboratory-based study.
  
  
  METHODS
  A panel of HNSCC cell lines was determined with anoikis assays, and orthotopic mouse experiments were performed. TP53 was sequenced. The shRNA knockdown and overexpression approaches were used for testing mutant p53 functions. The crystal structure of the p53 protein was analyzed using an in silico approach.
  
  
  RESULTS
  An anoikis-resistant cell line, Tu138, was found to have a proline-to-serine substitution at codon 151 of TP53, which results in loss of wild-type p53 transcriptional activity. Moreover, the mutant p53 was shown to promote anoikis resistance and soft agar growth. Using an in silico approach based on the crystal structure of wild-type p53 protein, substitution of proline by serine at position 151 would create a cavity in a hydrophobic pocket, the loss of van der Waals contacts, and the thermodynamically unfavorable placement of a polar group, the hydroxyl oxygen atom of the serine, within a hydrophobic region, all of which likely cause a locally altered structure.
  
  
  CONCLUSIONS
  Our data suggest that mutation at position 151 leads to a structural alteration, which results in significant functional changes in the p53 protein that impact tumor progression.
authors.affiliation: Departments of Head and Neck Surgery, University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Tong-Xin
authors.initials: TX
authors.lastname: Xie
authors.forename: Ge
authors.initials: G
authors.lastname: Zhou
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sano
authors.forename: Samar A
authors.initials: SA
authors.lastname: Jasser
authors.forename: Richard G
authors.initials: RG
authors.lastname: Brennan
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
mesh_terms: D000818:Animals; D023102:Anoikis / Q000235:genetics*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003062:Codon; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009374:Neoplasms, Experimental; D011392:Proline / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000235:genetics*; D000077195:Squamous Cell Carcinoma of Head and Neck; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D003062:Codon; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D012694:Serine; D011392:Proline