title: p27kip1 expression limits H-Ras-driven transformation and tumorigenesis by both canonical and non-canonical mechanisms.
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.
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Ilenia
authors: I
authors: Pellizzari
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.|Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Linda
authors: L
authors: Fabris
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Stefania
authors: S
authors: Berton
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Ilenia
authors: I
authors: Segatto
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Francesca
authors: F
authors: Citron
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Sara
authors: S
authors: D'Andrea
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Martina
authors: M
authors: Cusan
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Sara
authors: S
authors: Benevol
authors: Pathology Unit, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Tiziana
authors: T
authors: Perin
authors: Breast Surgery Unit, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Samuele
authors: S
authors: Massarut
authors: Pathology Unit, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Vincenzo
authors: V
authors: Canzonieri
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Monica
authors: M
authors: Schiappacassi
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Barbara
authors: B
authors: Belletti
authors: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors: Gustavo
authors: G
authors: Baldassarre
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050777:Stathmin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C436291:CDKN1B protein, human; D050777:Stathmin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases
keywords: H-Ras and K-Ras; cell cycle progression; metastasis; p27kip1; stathmin