@Article{Ferrarese_Harsh_GR_Yadav-Linea_splic_brain-2014,
  author =	 {Ferrarese, Roberto and Harsh, Griffith R. 4th and Yadav, 
                  Ajay K. and Bug, Eva and Maticzka, Daniel and Reichardt, 
                  Wilfried and Dombrowski, Stephen M. and Miller, Tyler E. and 
                  Masilamani, Anie P. and Dai, Fangping and Kim, Hyunsoo and 
                  Hadler, Michael and Scholtens, Denise M. and Yu, Irene L. Y. 
                  and Beck, Jurgen and Srinivasasainagendra, Vinodh and Costa, 
                  Fabrizio and Baxan, Nicoleta and Pfeifer, Dietmar and 
                  Elverfeldt, Dominik V. and Backofen, Rolf and Weyerbrock, 
                  Astrid and Duarte, Christine W. and He, Xiaolin and Prinz, 
                  Marco and Chandler, James P. and Vogel, Hannes and 
                  Chakravarti, Arnab and Rich, Jeremy N. and Carro, Maria S. 
                  and Bredel, Markus},
  title =	 {Lineage-specific splicing of a brain-enriched alternative 
                  exon promotes glioblastoma progression},
  journal =	 {J Clin Invest},
  year =	 {2014},
  volume =	 {124},
  number =	 {7},
  pages =	 {2861-2876},
  user =	 {backofen},
  pmid =	 {24865424},
  doi = 	 {10.1172/JCI68836},
  issn = 	 {0021-9738},
  issn = 	 {1558-8238},
  abstract =	 {Tissue-specific alternative splicing is critical for the 
                  emergence of tissue identity during development, yet the 
                  role of this process in malignant transformation is 
                  undefined. Tissue-specific splicing involves evolutionarily 
                  conserved, alternative exons that represent only a minority 
                  of the total alternative exons identified. Many of these 
                  conserved exons have functional features that influence 
                  signaling pathways to profound biological effect. Here, we 
                  determined that lineage-specific splicing of a 
                  brain-enriched cassette exon in the membrane-binding tumor 
                  suppressor annexin A7 (ANXA7) diminishes endosomal targeting 
                  of the EGFR oncoprotein, consequently enhancing EGFR 
                  signaling during brain tumor progression. ANXA7 exon 
                  splicing was mediated by the ribonucleoprotein PTBP1, which 
                  is normally repressed during neuronal development. PTBP1 was 
                  highly expressed in glioblastomas due to loss of a 
                  brain-enriched microRNA (miR-124) and to PTBP1 
                  amplification. The alternative ANXA7 splicing trait was 
                  present in precursor cells, suggesting that glioblastoma 
                  cells inherit the trait from a potential tumor-initiating 
                  ancestor and that these cells exploit this trait through 
                  accumulation of mutations that enhance EGFR signaling. Our 
                  data illustrate that lineage-specific splicing of a 
                  tissue-regulated alternative exon in a constituent of an 
                  oncogenic pathway eliminates tumor suppressor functions and 
                  promotes glioblastoma progression. This paradigm may offer a 
                  general model as to how tissue-specific regulatory 
                  mechanisms can reprogram normal developmental processes into 
                  oncogenic ones.}
}