title: Dysregulating IRES-dependent translation contributes to overexpression of oncogenic Aurora A Kinase.
abstract: Overexpression of the oncoprotein Aurora A kinase occurs in multiple types of cancer, often early during cell transformation. To identify the mechanism(s) contributing to enhanced Aurora A protein expression, a comparison between normal human lung fibroblast and breast epithelial cells to nontumorigenic breast (MCF10A and MCF12A) and tumorigenic breast (MCF-7) and cervical cell lines (HeLa S3) was performed. A subset of these immortalized lines (MCF10A, MCF12A, and HeLa S3) exhibited increased levels of Aurora A protein, independent of tumorigenicity. The increase in Aurora A protein in these immortalized cells was not due to increased transcription/RNA stability, protein half-life, or cap-dependent translation. Assays utilizing monocistronic and dicistronic RNA constructs revealed that the 5'-leader sequence of Aurora A contains an internal ribosomal entry site (IRES), which is regulated in a cell cycle-dependent manner, peaking in G2/M phase. Moreover, IRES activity was increased in the immortalized cell lines in which Aurora A protein expression was also enhanced. Additional studies indicated that the increased internal initiation is specific to the IRES of Aurora A and may be an early event during cancer progression. These results identify a novel mechanism contributing to Aurora A kinase overexpression.
  
  
  CONCLUSIONS
  The current study indicates that Aurora A kinase contributes to immortalization and tumorigenesis.
authors: Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, 6767 Bertner Ave, Houston, TX 77030, USA.
authors: Tara
authors: T
authors: Dobson
authors: Juan
authors: J
authors: Chen
authors: Les A
authors: LA
authors: Krushel
mesh_terms: D020121:5' Untranslated Regions; D064096:Aurora Kinase A / Q000235:genetics* / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D010442:Peptide Chain Initiation, Translational; D012315:RNA Caps / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D039561:Eukaryotic Initiation Factor-4E; D012315:RNA Caps; D012333:RNA, Messenger; C576917:AURKA protein, human; D064096:Aurora Kinase A
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