p53 Psi is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state

ŞENTÜRK Ş., Yao Z., Camiolo M., Stiles B., Rathod T., Walsh A. M., ...Daha Fazla

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, cilt.111, sa.32, 2014 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 111 Sayı: 32
  • Basım Tarihi: 2014
  • Doi Numarası: 10.1073/pnas.1321640111
  • Dergi Adı: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Anahtar Kelimeler: reactive oxygen species, cancer, MITOCHONDRIAL PERMEABILITY TRANSITION, EPITHELIAL-MESENCHYMAL TRANSITION, NEURAL STEM-CELLS, ARISTOLOCHIC ACID, SELF-RENEWAL, CANCER, CD44, TRANSLOCATION, TID1, PORE
  • Dokuz Eylül Üniversitesi Adresli: Hayır

Özet

Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3' splice site in intron 6 generates a unique p53 isoform, dubbed p53 Psi. At the molecular level, p53. is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53. attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability. Hence, we propose that p53. encodes a separation-of-function isoform that, although lacking canonical p53 tumor suppressor/transcriptional activities, is able to induce a prometastatic program in a transcriptionally independent manner.