Verteporfin inhibits YAP function through up-regulating 14-3-3σ sequestering YAP in the cytoplasm

You agree that the laws of the Kingdom of the Netherlands also apply to you. This condition only applies when you have lived in the Netherlands from the age of 4. Bis dahin galt das seit von Rot-Grün eingeführte so genannte Optionsrecht. Sorry, we couldn't find any pages containing.

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Your minor child can only apply for Dutch citizenship together with you. You then include your child on the form. Your child must be living in Netherlands at the time of the application and have a valid residence permit.

Children of 16 and 17 years of age must be present for the application. They must also indicate that they agree with the application. Is your child born during your naturalisation procedure after submitting the application, but before you have been granted Dutch nationality?

Your child must then live in the Netherlands with a valid residence permit for a non-temporary purpose of stay. You can fill in the option statement in the municipality where you live. You also fill out a form stating that you will make a declaration of solidarity. You will make this declaration during the naturalisation ceremony. The option procedure costs money. You pay when you make the option statement. You must also pay for children who are included with your option statement. Is the option statement not confirmed or do you withdraw your option statement?

You will not get any money back. It is possible that your name needs to be established. Establishing your name is required if you do not have a last name or or a first name. For example, if you have one name or multiple names without a distinction between the last name and first names. The municipality assesses whether you meet all the conditions. During these ceremonies the meaning of becoming a Dutch citizen is highlighted. You are obligated to go to the ceremony.

Was your child 16 years or older at at the time of the option statement? Then he is also obligated to go to the ceremony.

If your child is under the age of 16, he is not obligated to attend the naturalisation ceremony, but he is certainly allowed to be there. You will not become a Dutch citizen until you go to the ceremony and make the declaration of solidarity.

You agree that the laws of the Kingdom of the Netherlands also apply to you. The declaration of solidarity must be done in person. If you do not make the declaration of solidarity, you cannot become a Dutch citizen. At the ceremony, the decision, stating that you have become a Dutch citizen, will also be issued to you. If you cannot attend the first ceremony, you will get an invitation for a next ceremony.

You must attend the ceremony within 1 year following the decision. If you fail to do so, you will not receive Dutch nationality. After 1 year, you will need to submit a new application to become a Dutch citizen. What can and should you do as a Dutch citizen? You may apply for a Dutch passport or a Dutch identity card at the municipality in your place of residence. You may vote in provincial and national elections. You are no longer a foreign national. You will have the same rights as Dutch citizens.

You may, after a long stay abroad, come back to the Netherlands. You are an EU citizen. Cell proliferation was measured by SRB. The cellular location of YAP was determined by immunofluorescence staining.

The pictures at the right side are the enlargement of yellow frames in pictures at the left side. Verteporfin sequesters YAP in the cytosol. Cells were collected for western blotting with the indicated antibodies. Western blotting was performed with the indicated antibodies. Consistent with TP53 being required for the effects of Verteporfin on cell proliferation, the effects of Verteporfin were attenuated in TP53 null murine embryo fibroblasts Figure 6E.

It is important to note that Nou-1 endometrial cancer cell lines studied above are TP53 wild type. Western blotting was employed with the indicated antibodies. Cells were subjected to a RPPA assay. The graph at the left side is a screenshot of heatmap of RPPA data.

Verteporfin increases p53 levels. Cells were subjected to western blotting with the indicated antibodies. Cell proliferation was determined by SRB assay. The potential action of YAP as a tumor suppressor may be independent of its transcriptional co-activator function with YAP acting as a scaffolding protein in the cytosol [ 18 - 22 ]. Recent literature reported YAP overexpression is not only an early event in rat and human liver tumorigenesis but also a critical event in the clonal expansion of carcinogen-initiated hepatocytes and oval cells, and the disruption of YAP-TEAD interaction induced by Verteporfin may provide an important approach for the treatment of YAP-overexpressing cancers [ 23 ].

Nuclear YAP expression was associated with poor outcome in urothelial cell carcinoma patients who received perioperative chemotherapy. Verteporfin inhibiting YAP function inhibited tumor cell proliferation and restored sensitivity to cisplatin [ 24 ].

Thus inhibition of YAP levels or function with Verteporfin warrants exploration as a therapeutic approach particularly in cancer with wild type TP53 where the effects of Verteporfin are most clearly manifest. Our studies with endometrial cells lines, the association of YAP levels with clinical characteristics in endometrial cancer and the observation that TP53 is wild type in most type 1 endometrial cancers, suggest that Verteporfin may be effective in this disease.

Verteporfin has been used to treat patients as a photosensitizer with limited toxicity. Recent evidence that Verteporfin can alter functions associated with tumor pathophysiology including autophagy and inhibition of YAP function independent of its action as a photosensitizer support its evaluation as a cancer therapeutic [ 9 - 11 ].

They regulate many critical events such as autophagy [ 25 ], apoptosis [ 26 ], cell cycle progression [ 27 ], DNA damage response [ 28 ], cytoskeletal rearrangements [ 29 ], and transcriptional regulation [ 30 ] refs please. As proteins regulate autophagy, this raises the intriguing possibility that the effects of Verteporfin on autophagy may be secondary to effects of Verteporfin on inducing family members.

The major activity of proteins is thought to be the sequestration of phosphorylated proteins in the cytosol with subsequent targeting for degradation in the proteasome. The different proteins sequester unique sets of targets. Thus family proteins sequester multiple key oncogenic regulators. Thus the effects of Verteporfin may be most clearly manifest in cells with wild type p Taken together our studies suggest that repurposing Verteporfin as a cancer therapeutic may demonstrate monotherapy or more likely combination therapy activity in in tumors where YAP signaling is critical to tumor pathophysiology and in particular in tumors where p53 is wild type.

Type 1 endometrial cancer is an obvious candidate for the therapeutic evaluation of Verteporfin. National Center for Biotechnology Information , U. Am J Cancer Res. Author information Article notes Copyright and License information Disclaimer.

Received Nov 20; Accepted Nov This article has been cited by other articles in PMC. Abstract Yes-associated protein YAP , the central mediator of Hippo pathway, not only regulates a diversity of cellular processes during development but also plays a pivotal role in tumorigenesis.

Introduction The Yes-associated protein YAP , a key downstream effector in the HIPPO signaling cascade, which was originally identified in Drosophila, has emerged as a major contributor to cancer pathophysiology [ 1 - 3 ].

Sulforhodamine B assay Cells were seeded in well plates and then treated as described. Results YAP1 is overexpressed in women cancers and promotes cell proliferation Using the cancer genome atlas data http: Open in a separate window. Disclosure of conflict of interest None. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Oh H, Irvine KD. The hippo signaling pathway in development and cancer.

The Hippo-YAP pathway in organ size control and tumorigenesis: J Natl Cancer Inst.

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