title: Prolyl-isomerase Pin1 controls Notch3 protein expression and regulates T-ALL progression.
abstract: Deregulated Notch signaling is associated with T-cell Acute Lymphoblastic Leukemia (T-ALL) development and progression. Increasing evidence reveals that Notch pathway has an important role in the invasion ability of tumor cells, including leukemia, although the underlying molecular mechanisms remain mostly unclear. Here, we show that Notch3 is a novel target protein of the prolyl-isomerase Pin1, which is able to regulate Notch3 protein processing and to stabilize the cleaved product, leading to the increased expression of the intracellular domain (N3IC), finally enhancing Notch3-dependent invasiveness properties. We demonstrate that the combined inhibition of Notch3 and Pin1 in the Notch3-overexpressing human leukemic TALL-1 cells reduces their high invasive potential, by decreasing the expression of the matrix metalloprotease MMP9. Consistently, Pin1 depletion in a mouse model of Notch3-induced T-ALL, by reducing N3IC expression and signaling, impairs the expansion/invasiveness of CD4(+)CD8(+) DP cells in peripheral lymphoid and non-lymphoid organs. Notably, in in silico gene expression analysis of human T-ALL samples we observed a significant correlation between Pin1 and Notch3 expression levels, which may further suggest a key role of the newly identified Notch3-Pin1 axis in T-ALL aggressiveness and progression. Thus, combined suppression of Pin1 and Notch3 proteins may be exploited as an additional target therapy for T-ALL.
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Franciosa
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Diluvio
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: F Del
authors.initials: FD
authors.lastname: Gaudio
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: M V
authors.initials: MV
authors.lastname: Giuli
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Palermo
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Grazioli
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: A F
authors.initials: AF
authors.lastname: Campese
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Talora
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Bellavia
authors.affiliation: Department of Radiological, Oncological and Pathological Sciences, Sapienza University, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: D'Amati
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Besharat
authors.affiliation: Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Nicoletti
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, CA, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Siebel
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Choy
authors.affiliation: Laboratorio Nazionale CIB Area Science Park Trieste, University of Trieste, Trieste, Italy.|Department Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rustighi
authors.affiliation: Laboratorio Nazionale CIB Area Science Park Trieste, University of Trieste, Trieste, Italy.|Department Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: G Del
authors.initials: GD
authors.lastname: Sal
authors.affiliation: Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.|Institute Pasteur-Foundation Cenci Bolognetti, Sapienza University, Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Checquolo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009367:Neoplasm Staging; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D000071656:Receptor, Notch3 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; C000606846:PIN1 protein, human