p27kip1 expression limits H-Ras-driven transformation and tumorigenesis by both canonical and non-canonical mechanisms

Ilenia Pellizzari, Linda Fabris, Stefania Berton, Ilenia Segatto, Francesca Citron, Sara D'Andrea, Martina Cusan, Sara Benevol, Tiziana Perin, Samuele Massarut, Vincenzo Canzonieri, Monica Schiappacassi, Barbara Belletti, Gustavo Baldassarre

Research output: Contribution to journalArticle

Abstract

The tumor suppressor protein p27Kip1 plays a pivotal role in the control of cell growth and metastasis formation. Several studies pointed to different roles for p27Kip1 in the control of Ras induced transformation, although no explanation has been provided to elucidate these differences. We recently demonstrated that p27kip1 regulates H-Ras activity via its interaction with stathmin. Here, using in vitro and in vivo models, we show that p27kip1 is an important regulator of Ras induced transformation. In H-RasV12 transformed cells, p27kip1 suppressed cell proliferation and tumor growth via two distinct mechanisms: 1) inhibition of CDK activity and 2) impairment of MT-destabilizing activity of stathmin. Conversely, in K-Ras4BV12 transformed cells, p27kip1 acted mainly in a CDK-dependent but stathmin-independent manner. Using human cancer-derived cell lines and primary breast and sarcoma samples, we confirmed in human models what we observed in mice. Overall, we highlight a pathway, conserved from mouse to human, important in the regulation of H-Ras oncogenic activity that could have therapeutic and diagnostic implication in patients that may benefit from anti-H-Ras therapies.

Original languageEnglish
Pages (from-to)64560-64574
Number of pages15
JournalOncotarget
Volume7
Issue number40
DOIs
Publication statusPublished - 2016

Keywords

  • Cell cycle progression
  • H-Ras and K-Ras
  • Metastasis
  • P27Kip1
  • Stathmin

ASJC Scopus subject areas

  • Oncology

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