Cell cycle regulated expression and phosphorylation of hpttg proto-oncogene product

Ramos‐Morales, Francisco; Domı́nguez, Africa; Romero, Fráncisco; Luna, Rosa; Multon, Marie-Christine; Pintor‐Toro, José Antonio; Tortolero, Marı́a

doi:10.1038/sj.onc.1203320

Cited by 107 publications

(139 citation statements)

References 43 publications

(47 reference statements)

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“…Forty-eight hours after paclitaxel treatment, all of these proteins decreased in PC3 cells and remain similar (or even higher in the case of phospho-histone H3) in LNCaP cells. It has been described that PTTG1 becomes phosphorylated in mitosis (9) and, interestingly, paclitaxel treatment induces PTTG1 phosphorylation in both cell lines, observed as a PTTG1 band shift, but the protein decreases in paclitaxel-treated PC3 cells and accumulates in paclitaxel-treated LNCaP cells (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

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Prostate Cancer Cell Response to Paclitaxel Is Affected by Abnormally Expressed Securin PTTG1

Castilla

Medina

et al. 2014

Molecular Cancer Therapeutics

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PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippageprone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting. Mol Cancer Ther; 13(10); 2372-83. Ó2014 AACR.

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Section: Resultsmentioning

confidence: 99%

“…Its expression level varies within the cell cycle, reaching the maximum in G 2 -M (9). Subcutaneous injection of PTTG1-transfected cells into nude mice has been shown to induce tumors formation.…”

Section: Introductionmentioning

confidence: 99%

Prostate Cancer Cell Response to Paclitaxel Is Affected by Abnormally Expressed Securin PTTG1

Castilla

Medina

et al. 2014

Molecular Cancer Therapeutics

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“…Moreover, Shc was shown to be involved in activation of c-Rel and mitogen-activated protein kinase, and it is required for TCRinduced interleukin-2 production (67). Vav1 also binds multiple signaling proteins through its SH2, SH3, and proline-rich regions, including adapter molecules such as Grb2, Crk, and Shc (68,69) and signaling proteins such as ZAP-70 (70) and SLP-76 (71,72). The functional significance of the interaction of Vav1 with the adapter proteins is unknown as yet.…”

Section: Discussionmentioning

confidence: 99%

Vav1 and Ly-GDI Two Regulators of Rho GTPases, Function Cooperatively as Signal Transducers in T Cell Antigen Receptor-induced Pathways

Groysman

Hornstein

Alcover

et al. 2002

Journal of Biological Chemistry

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The Rho family GTPases are pivotal for T cell signaling; however, the regulation of these proteins is not fully known. One well studied regulator of Rho GTPases is Vav1; a hematopoietic cell-specific guanine nucleotide exchange factor critical for signaling in T cells, including stimulation of the nuclear factor of activated T cells (NFAT). Surprisingly, Vav1 associates with Ly-GDI, a hematopoietic cell-specific guanine nucleotide dissociation inhibitor of Rac. Here, we studied the functional significance of the interaction between Vav1 and Ly-GDI in T cells. Upon organization of the immunological synapse, both Ly-GDI and Vav1 relocalize to T cell extensions in contact with the antigen-presenting cell. Ly-GDI is phosphorylated on tyrosine residues following T cell receptor stimulation, and it associates with the Src homology 2 region of an adapter protein, Shc. In addition, the interaction between Ly-GDI and Vav1 requires tyrosine phosphorylation. Overexpression of Ly-GDI alone is inhibitory to NFAT stimulation and calcium mobilization. However, when co-expressed with Vav1, Ly-GDI enhances Vav1 induction of NFAT activation, phospholipase C␥ phosphorylation, and calcium mobilization. Moreover, Ly-GDI does not alter the regulation of these phenomena when coexpressed with oncogenic Vav1. Since oncogenic Vav1 does not bind Ly-GDI, this suggests that the functional cooperativity of Ly-GDI and Vav1 is dependent upon their association. Thus, our data suggest that the interaction of Vav1 and Ly-GDI creates a fine tuning mechanism for the regulation of intracellular signaling pathways leading to NFAT stimulation.The Rho GTPase proteins participate in cellular processes such as cell cycle, movement and migration, metabolism, survival, proliferation, and differentiation (1-4). Rho GTPase proteins cycle between the GDP-bound inactive and GTP-bound active forms. Extracellular signals can affect Rho GTPase activity through at least three types of regulatory molecules: the GTPase-activating proteins that stimulate conversion from the GTP-bound form to the GDP-bound form; the GDP/GTP exchange factors (GEFs), 1 which facilitate the shift from the GDP-bound form to the GTP-bound form; and the GDP dissociation inhibitors (GDIs), which block GDP dissociation from Rho GTPases, thus maintaining the inactive state (4). Despite accumulating experimental evidence, many details of the regulation of GDP/GTP exchange remain to be elucidated.One of the well studied GEFs for Rho GTPases is Vav1, a hematopoietic cell-specific signal transducer protein (5, 6). Vav1 contains several characteristic structural motifs that enable its function as a signal transducer protein. In fact, Vav1 and the other ubiquitously expressed members of the Vav family of proteins (Vav2 and Vav3) are the only known Rho GEFs that have SH2 domains, suggesting that their GEF activity is regulated by tyrosine phosphorylation (7-10).One of the best studied roles of Vav1 is as a signal transducer in activated T cells. TCR stimulation with antigen or with cross-linking anti...

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“…Securin is a cell cycle -regulated protein with minimal levels in G 1 (30); hence, we tested if dicoumarol provoked cell cycle arrest in G 1 phase in HCT116. Increasing amounts of dicoumarol translated into a slightly greater proportion of cells in G 1 (Table 1).…”

Section: Concentrations Of Dicoumarol Above 100mentioning

confidence: 99%

Dicoumarol down-regulates human PTTG1/Securin mRNA expression through inhibition of Hsp90

Hernández

López-Lluch²,

Bernal³

et al. 2008

Molecular Cancer Therapeutics

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Cell cycle regulated expression and phosphorylation of hpttg proto-oncogene product

Cited by 107 publications

References 43 publications

Prostate Cancer Cell Response to Paclitaxel Is Affected by Abnormally Expressed Securin PTTG1

Prostate Cancer Cell Response to Paclitaxel Is Affected by Abnormally Expressed Securin PTTG1

Vav1 and Ly-GDI Two Regulators of Rho GTPases, Function Cooperatively as Signal Transducers in T Cell Antigen Receptor-induced Pathways

Dicoumarol down-regulates human PTTG1/Securin mRNA expression through inhibition of Hsp90

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