Downregulation of protein tyrosine phosphatase PTPL1 alters cell cycle and upregulates invasion-related genes in prostate cancer cells

Castilla, Carolina; Flores, M. Luz; Conde, José M.; Medina, Rafael; Torrubia, Francisco; Japón, Miguel Á.; Sáez, Carmen

doi:10.1007/s10585-012-9455-7

Cited by 18 publications

(13 citation statements)

References 36 publications

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“…Thus, our findings that EphrinB1 phosphorylation is regulated throughout the cell cycle are consistent with restriction of Erk1/2 signaling during mitosis. In addition, knock-down of PTPN13 in prostate cancer cell lines increases G0/G1 phase cells and decreases S and G2/M phase cells [ 19 ], also suggesting that PTPN13 activity modulates cell cycle progression. With respect to chemotherapeutics, we demonstrate that expression of EphrinB1 in the context of compromised PTPN13 modulates the cellular response to paclitaxel in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, decreased PTPN13 expression correlates with changes in cellular proliferation and invasive characteristics in multiple epithelial cells in vitro as well as in tumors in vivo. Taken together, these data suggest not only that PTPN13 is a tumor suppressor, but also that loss of PTPN13 expression or function affects mitosis [ 19 - 27 ]. Its localization pattern throughout the cell cycle is consistent with this idea and suggests that PTPN13 may directly regulate mitosis.…”

Section: Introductionmentioning

confidence: 99%

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EphrinB1: novel microtubule associated protein whose expression affects taxane sensitivity

et al. 2014

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Microtubules (MTs) are components of the cytoskeleton made up of polymerized alpha and beta tubulin dimers. MT structure and function must be maintained throughout the cell cycle to ensure proper execution of mitosis and cellular homeostasis. The protein tyrosine phosphatase, PTPN13, localizes to distinct compartments during mitosis and cytokinesis. We have previously demonstrated that the HPV16 E6 oncoprotein binds PTPN13 and leads to its degradation. Thus, we speculated that HPV infection may affect cellular proliferation by altering the localization of a PTPN13 phosphatase substrate, EphrinB1, during mitosis. Here we report that EphrinB1 co-localizes with MTs during all phases of the cell cycle. Specifically, a cleaved, unphosphorylated EphrinB1 fragment directly binds tubulin, while its phosphorylated form lacks MT binding capacity. These findings suggest that EphrinB1 is a novel microtubule associated protein (MAP). Importantly, we show that in the context of HPV16 E6 expression, EphrinB1 affects taxane response in vitro. We speculate that this reflects PTPN13's modulation of EphrinB1 phosphorylation and suggest that EphrinB1 is an important contributor to taxane sensitivity/resistance phenotypes in epithelial cancers. Thus, HPV infection or functional mutations of PTPN13 in non-viral cancers may predict taxane sensitivity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

EphrinB1: novel microtubule associated protein whose expression affects taxane sensitivity

et al. 2014

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“…In contrast, normal mouse epithelial cells transfected with oncogenic Ras and depleted of PTPL1 were able to maintain anchorage-independent growth and grow in immuno-competent mice [33] supporting a tumor-suppressor role for PTPL1. Studies in cancers of epithelial origin line breast [8] and prostate [34] support the tumor-suppressor role. While in ES cells which are of mesenchymal origin we observe an oncogenic role for PTPL1.…”

Section: Discussionmentioning

confidence: 99%

Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1

Abaan

Hendriks

Üren

et al. 2013

Experimental Cell Research

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Identification of Protein Tyrosine Phosphatase (PTP) substrates is critical in understanding cellular role in normal cells as well as cancer cells. We have previously shown that reduction of PTPL1 protein levels in Ewings sarcoma (ES) inhibit cell growth and tumorigenesis. Therefore, we sought to identify novel PTPL1 substrates that may be important for tumorigenesis. In this current work, we demonstrated that mouse embryonic fibroblasts without PTPL1 catalytic activity fail to form foci when transfected with oncogenes. We proved that catalytic activity of PTPL1 is important for ES cell growth. Using a substrate-trapping mutant of PTPL1 we identified putative PTPL1 substrates by mass-spectrometry. One of these putative substrates was characterized as Valosin Containing Protein (VCP/p97). Using multiple biochemical assays we validated VCP as a novel substrate of PTPL1. We also provide evidence that tyrosine phosphorylation of VCP might be important for its midbody localization during cytokinesis. In conclusion, our work identifies VCP as a new substrate for PTPL1, which may be important in cellular transformation. Our investigation link an oncogenic transcription factor EWS-FLI1, with a key transcriptional target protein tyrosine phosphatase PTPL1, and its substrate VCP. Given our observation that PTPL1 catalytic activity is important for cell transformation, our results may also suggest that VCP regulation by PTPL1 might be important for tumorigenesis.

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“…18,19 Cells were lysed in RIPA buffer (Sigma). The cell lysates were quantified using a BCA protein assay kit (Pierce), and an equal amount of protein (10 mg) was resolved by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred onto nitrocellulose membranes (Bio-Rad).…”

Section: Western Blotmentioning

confidence: 99%

Lentivirus Vector-Mediated Knockdown of Erythropoietin-Producing Hepatocellular Carcinoma Receptors B4 Inhibits Laser-Induced Choroidal Neovascularization

Zhao²,

Wang³

et al. 2013

Journal of Ocular Pharmacology and Therapeutics

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Purpose: To evaluate the efficacy of erythropoietin-producing hepatocellular carcinoma receptors B4 (EphB4) knockdown on the development of laser-induced choroidal neovascularization (CNV) in vivo. Methods: We constructed recombinant lentiviral vectors (Lv) Lv-shRNA-EphB4 to specifically knock down the expression of EphB4. The mRNA and protein expression of EphB4 was investigated by real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot. CNV was induced by laser photocoagulation in C57BL/6 mice. The mice were then randomly assigned to be intravitreally injected with phosphate-buffered saline (PBS), Lv-shRNA-EphB4 recombinant lentivirus, or an unrelated shRNA recombinant lentivirus (pFU LV-shRNA-NC). An uninjected group was used as the control. Fundus fluorescein angiography (FFA), histologic analysis, and choroidal flat mounts analysis were applied to evaluate the inhibition of CNV after an intravitreal injection. Results: Transfection of Lv-shRNA-EphB4 led to the knockdown of EphB4, and EphB4 mRNA was downregulated by about 80%. FFA and histologic analysis revealed that the leakage areas and the mean thickness of CNV were much smaller in the Lv-shRNA-EphB4 group than in the PBS-treated, pFU Lv-shRNA-NC group and the non-injection group. Choroidal flat mounts showed significantly less leakage and smaller leakage areas in the Lv-shRNA-EphB4 group than those in other groups. Conclusion: Knocking down the expression of EphB4 exerts an inhibitory effect on CNV in vivo. It may provide a potential strategy for the treatment of CNV.

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Downregulation of protein tyrosine phosphatase PTPL1 alters cell cycle and upregulates invasion-related genes in prostate cancer cells

Cited by 18 publications

References 36 publications

EphrinB1: novel microtubule associated protein whose expression affects taxane sensitivity

EphrinB1: novel microtubule associated protein whose expression affects taxane sensitivity

Valosin containing protein (VCP/p97) is a novel substrate for the protein tyrosine phosphatase PTPL1

Lentivirus Vector-Mediated Knockdown of Erythropoietin-Producing Hepatocellular Carcinoma Receptors B4 Inhibits Laser-Induced Choroidal Neovascularization

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