@phdthesis{Hanselmann2023,
  author    = {Hanselmann, Steffen},
  title     = {PRC1 serves as a microtubule-bundling protein and is a potential therapeutic target for lung cancer},
  doi       = {10.25972/OPUS-26631},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266314},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Protein regulator of cytokinesis 1 (PRC1) is a microtubule-associated protein with essential roles in mitosis and cytokinesis. Furthermore, the protein is highly expressed in several cancer types which is correlated with aneuploidy and worse patient outcome. In this study it was investigated, whether PRC1 is a potential target for lung cancer as well as its possible nuclear role. Elevated PRC1 expression was cell cycle-dependent with increasing levels from S-phase to G2/M-phase of the cell cycle. Thereby, PRC1 localized at the nucleus during interphase and at the central spindle and midbody during mitosis and cytokinesis. Genome-wide expression profiling by RNA sequencing of ectopically expressed PRC1 resulted in activation of the p53 pathway. A mutant version of PRC1, that is unable to enter the nucleus, induced the same gene sets as wildtype PRC1, suggesting that PRC1 has no nuclear-specific functions in lung cancer cells. Finally, PRC1 overexpression leads to proliferation defects, multi-nucleation, and enlargement of cells which was directly linked to microtubule-bundling within the cytoplasm. For analysis of the requirement of PRC1 in lung cancer, different inducible cell lines were generated to deplete the protein by RNA interference (RNAi) in vitro. PRC1 depletion caused proliferation defects and cytokinesis failures with increased numbers of bi- and multi-nucleated cells compared to non-induced lung cancer cells. Importantly, effects in control cells were less severe as in lung cancer cells. Finally, p53 wildtype lung cancer cells became senescent, whereas p53 mutant cells became apoptotic upon PRC1 depletion. PRC1 is also required for tumorigenesis in vivo, which was shown by using a mouse model for non-small cell lung cancer driven by oncogenic K-RAS and loss of p53. Here, lung tumor area, tumor number, and high-grade tumors were significantly reduced in PRC1 depleted conditions by RNAi. In this study, it is shown that PRC1 serves as a microtubule-bundling protein with essential roles in mitosis and cytokinesis. Expression of the protein needs to be tightly regulated to allow unperturbed proliferation of lung cancer cells. It is suggested that besides phosphorylation of PRC1, the nuclear localization might be a protective mechanism for the cells to prevent perinuclear microtubule-bundling. In conclusion, PRC1 could be a potential target of lung cancer as mono therapy or in combination with a chemotherapeutic agent, like cisplatin, which enhanced the negative effects on proliferation of lung cancer cells in vitro.},
  language  = {en}
}
@article{MainzSarhanRothetal.2022,
  author    = {Mainz, Laura and Sarhan, Mohamed A. F. E. and Roth, Sabine and Sauer, Ursula and Maurus, Katja and Hartmann, Elena M. and Seibert, Helen-Desiree and Rosenwald, Andreas and Diefenbacher, Markus E. and Rosenfeldt, Mathias T.},
  title     = {Autophagy blockage reduces the incidence of pancreatic ductal adenocarcinoma in the context of mutant Trp53},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {10},
  journal   = {Frontiers in Cell and Developmental Biology},
  issn      = {2296-634X},
  doi       = {10.3389/fcell.2022.785252},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266005},
  year      = {2022},
  abstract  = {Macroautophagy (hereafter referred to as autophagy) is a homeostatic process that preserves cellular integrity. In mice, autophagy regulates pancreatic ductal adenocarcinoma (PDAC) development in a manner dependent on the status of the tumor suppressor gene Trp53. Studies published so far have investigated the impact of autophagy blockage in tumors arising from Trp53-hemizygous or -homozygous tissue. In contrast, in human PDACs the tumor suppressor gene TP53 is mutated rather than allelically lost, and TP53 mutants retain pathobiological functions that differ from complete allelic loss. In order to better represent the patient situation, we have investigated PDAC development in a well-characterized genetically engineered mouse model (GEMM) of PDAC with mutant Trp53 (Trp53\(^{R172H}\)) and deletion of the essential autophagy gene Atg7. Autophagy blockage reduced PDAC incidence but had no impact on survival time in the subset of animals that formed a tumor. In the absence of Atg7, non-tumor-bearing mice reached a similar age as animals with malignant disease. However, the architecture of autophagy-deficient, tumor-free pancreata was effaced, normal acinar tissue was largely replaced with low-grade pancreatic intraepithelial neoplasias (PanINs) and insulin expressing islet β-cells were reduced. Our data add further complexity to the interplay between Atg7 inhibition and Trp53 status in tumorigenesis.},
  language  = {en}
}
@article{PrietoGarciaTomaškovićShahetal.2021,
  author    = {Prieto-Garcia, Cristian and Tomašković, Ines and Shah, Varun Jayeshkumar and Dikic, Ivan and Diefenbacher, Markus},
  title     = {USP28: oncogene or tumor suppressor? a unifying paradigm for squamous cell carcinoma},
  series = {Cells},
  volume    = {10},
  journal   = {Cells},
  number    = {10},
  issn      = {2073-4409},
  doi       = {10.3390/cells10102652},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248409},
  year      = {2021},
  abstract  = {Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.},
  language  = {en}
}
@article{DjuzenovaFischerKatzeretal.2021,
  author    = {Djuzenova, Cholpon S. and Fischer, Thomas and Katzer, Astrid and Sisario, Dmitri and Korsa, Tessa and Streussloff, Gudrun and Sukhorukov, Vladimir L. and Flentje, Michael},
  title     = {Opposite effects of the triple target (DNA-PK/PI3K/mTOR) inhibitor PI-103 on the radiation sensitivity of glioblastoma cell lines proficient and deficient in DNA-PKcs},
  series = {BMC Cancer},
  volume    = {21},
  journal   = {BMC Cancer},
  doi       = {10.1186/s12885-021-08930-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265826},
  year      = {2021},
  abstract  = {Background: Radiotherapy is routinely used to combat glioblastoma (GBM). However, the treatment efficacy is often limited by the radioresistance of GBM cells. Methods: Two GBM lines MO59K and MO59J, differing in intrinsic radiosensitivity and mutational status of DNA-PK and ATM, were analyzed regarding their response to DNA-PK/PI3K/mTOR inhibition by PI-103 in combination with radiation. To this end we assessed colony-forming ability, induction and repair of DNA damage by gamma H2AX and 53BP1, expression of marker proteins, including those belonging to NHEJ and HR repair pathways, degree of apoptosis, autophagy, and cell cycle alterations. Results: We found that PI-103 radiosensitized MO59K cells but, surprisingly, it induced radiation resistance in MO59J cells. Treatment of MO59K cells with PI-103 lead to protraction of the DNA damage repair as compared to drug-free irradiated cells. In PI-103-treated and irradiated MO59J cells the foci numbers of both proteins was higher than in the drug-free samples, but a large portion of DNA damage was quickly repaired. Another cell line-specific difference includes diminished expression of p53 in MO59J cells, which was further reduced by PI-103. Additionally, PI-103-treated MO59K cells exhibited an increased expression of the apoptosis marker cleaved PARP and increased subG1 fraction. Moreover, irradiation induced a strong G2 arrest in MO59J cells (similar to 80\% vs. similar to 50\% in MO59K), which was, however, partially reduced in the presence of PI-103. In contrast, treatment with PI-103 increased the G2 fraction in irradiated MO59K cells. Conclusions: The triple-target inhibitor PI-103 exerted radiosensitization on MO59K cells, but, unexpectedly, caused radioresistance in the MO59J line, lacking DNA-PK. The difference is most likely due to low expression of the DNA-PK substrate p53 in MO59J cells, which was further reduced by PI-103. This led to less apoptosis as compared to drug-free MO59J cells and enhanced survival via partially abolished cell-cycle arrest. The findings suggest that the lack of DNA-PK-dependent NHEJ in MO59J line might be compensated by DNA-PK independent DSB repair via a yet unknown mechanism.},
  language  = {en}
}
@phdthesis{Roth2020,
  author    = {Roth, Markus},
  title     = {Etablierung eines isogenen Zelllinienmodells zur Untersuchung der Bedeutung mono- und biallelischer TP53-Inaktivierungen beim Multiplen Myelom},
  doi       = {10.25972/OPUS-20893},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208939},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Trotz der Fortschritte in der Therapie des Multiplen Myeloms und des stetig wachsenden Arsenals effektiver anti-MM-Medikamente muss ein Teil der Patienten mit bestimmten zytogenetischen Ver{\"a}nderungen der Tumorzellen nach wie vor der Hochrisiko-Gruppe zugeordnet werden und hat eine Lebens-erwartung von nur wenigen Jahren. Einer der ung{\"u}nstigsten prognostischen Marker ist die Inaktivierung des Tumorsuppressorgens TP53 durch Mutationen des Gens oder Deletionen des kurzen Arms von Chromosom 17, del(17p). Diese wird h{\"a}ufig mit einer Chemoresistenz der entarteten Plasmazellen in Verbindung gebracht. In der vorliegenden Arbeit gelang es mittels des CRISPR/Cas9-Systems TP53-L{\"a}sionen zu erzeugen und isogene Klone der TP53wt/wt Zelllinie AMO-1 zu generieren. Diese wurden anhand der Sequenzanalysen von beiden TP53-Allelen den Gruppen der biallelisch TP53-inaktivierten, der monoallelisch TP53-inaktivierten und der TP53wt/wt Klone zugeordnet. Das gruppenspezifische Verhalten der Klone aller drei Gruppen hinsichtlich deren Expression von p53, p21 und Mdm2 unterstrich die Validit{\"a}t des etablierten Zelllinienmodells zur Untersuchung der Bedeutung von TP53-L{\"a}sionen beim Multiplen Myelom. Neben einer kompletten Ausschaltung durch biallelische TP53-Inaktivierung zeigten die Ergebnisse der vorliegenden Arbeit auch eine Haploinsuffizienz des p53-Systems. Diese {\"a}ußerte sich in einer Abschw{\"a}chung der Nutlin-3A-abh{\"a}ngigen p53-, p21- und Mdm2-Induktion bereits nach Inaktivierung eines TP53-Allels durch Frameshift-Mutation. Korrelierend zu dem Proteinexpressions¬muster konnte eine zunehmende Resistenzentwicklung der Klone je nach Grad der TP53-Inaktivierung (mono- bzw. biallelisch) gegen Nutlin 3A sowie genotoxische Substanzen nachgewiesen werden, w{\"a}hrend die Sensibilit{\"a}t der MM-Zellen gegen Proteasominhibitoren unbeeintr{\"a}chtigt blieb. Einschr{\"a}nkungen hinsichtlich der {\"U}bertragbarkeit der Ergebnisse der vorliegenden Arbeit auf das Multiple Myelom im Allgemeinen bestehen in dem Umstand, dass die beschriebenen Beobachtungen lediglich an einer einzigen MM-Zelllinie gemacht werden konnten. Dies ist durch die geringe Auswahl an TP53wt/wt MM-Zelllinien, die zudem noch oft eine schlechte Transfektabilit{\"a}t und niedrige Zellteilungsrate nach Einzelzellselektion aufweisen, bedingt. Die an der Zelllinie AMO-1 gemachten Beobachtungen stehen in Einklang mit der in klinischen Studien festgestellten Verk{\"u}rzung des progressionsfreien- (PFS) und Gesamt-{\"U}berlebens (OS) bei MM-Patienten mit TP53-Alterationen. Die zunehmende Chemoresistenz der malignen Plasmazellen nach mono- bzw. biallelischer TP53-Inaktivierung kann als Grund f{\"u}r die Akkumulation entsprechender Klone im Rezidiv und in fortgeschrittenen Krankheitsstadien des MM angesehen werden. Mittels m{\"o}glichst umfassender Erfassung des genauen TP53-L{\"a}sions-Status in zuk{\"u}nftigen klinischen Studien zu multiplen Zeitpunkten des Krankheitsverlaufs k{\"o}nnte der Einfluss verschiedener, in der Therapie des MM zum Einsatz kommender Substanzen auf die Selektion bzw. die Unterdr{\"u}ckung besonders virulenter Subklone mit TP53-L{\"a}sionen untersucht werden.},
  subject      = {Plasmozytom},
  language  = {de}
}
@article{ThiemHesbacherKneitzetal.2019,
  author    = {Thiem, Alexander and Hesbacher, Sonja and Kneitz, Hermann and di Primio, Teresa and Heppt, Markus V. and Hermanns, Heike M. and Goebeler, Matthias and Meierjohann, Svenja and Houben, Roland and Schrama, David},
  title     = {IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression},
  series = {Journal of Experimental \& Clinical Cancer Research},
  volume    = {38},
  journal   = {Journal of Experimental \& Clinical Cancer Research},
  doi       = {10.1186/s13046-019-1403-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201016},
  pages     = {397},
  year      = {2019},
  abstract  = {Background Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma. Methods We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway. Results For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53\(^{L22Q,W23S}\), a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53\(^{L22Q,W23S}\) in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression. Conclusions While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.},
  language  = {en}
}
@phdthesis{Kaymak2019,
  author    = {Kaymak, Irem},
  title     = {Identification of metabolic liabilities in 3D models of cancer},
  doi       = {10.25972/OPUS-18154},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181544},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Inefficient vascularisation of solid tumours leads to the formation of oxygen and nutrient gradients. In order to mimic this specific feature of the tumour microenvironment, a multicellular tumour spheroid (SPH) culture system was used. These experiments were implemented in p53 isogenic colon cancer cell lines (HCT116 p53 +/+ and HCT116 p53-/-) since Tp53 has important regulatory functions in tumour metabolism. First, the characteristics of the cells cultured as monolayers and as spheroids were investigated by using RNA sequencing and metabolomics to compare gene expression and metabolic features of cells grown in different conditions. This analysis showed that certain features of gene expression found in tumours are also present in spheroids but not in monolayer cultures, including reduced proliferation and induction of hypoxia related genes. Moreover, comparison between the different genotypes revealed that the expression of genes involved in cholesterol homeostasis is induced in p53 deficient cells compared to p53 wild type cells and this difference was only detected in spheroids and tumour samples but not in monolayer cultures. In addition, it was established that loss of p53 leads to the induction of enzymes of the mevalonate pathway via activation of the transcription factor SREBP2, resulting in a metabolic rewiring that supports the generation of ubiquinone (coenzyme Q10). An adequate supply of ubiquinone was essential to support mitochondrial electron transport and pyrimidine biosynthesis in p53 deficient cancer cells under conditions of metabolic stress. Moreover, inhibition of the mevalonate pathway using statins selectively induced oxidative stress and apoptosis in p53 deficient colon cancer cells exposed to oxygen and nutrient deprivation. This was caused by ubiquinone being required for electron transfer by dihydroorotate dehydrogenase, an essential enzyme of the pyrimidine nucleotide biosynthesis pathway. Supplementation with exogenous nucleosides relieved the demand for electron transfer and restored viability of p53 deficient cancer cells under metabolic stress. Moreover, the mevalonate pathway was also essential for the synthesis of ubiquinone for nucleotide biosynthesis to support growth of intestinal tumour organoids. Together, these findings highlight the importance of the mevalonate pathway in cancer cells and provide molecular evidence for an enhanced sensitivity towards the inhibition of mitochondrial electron transfer in tumour-like metabolic environments.},
  subject      = {Tumor},
  language  = {en}
}
@article{DjuzenovaFiedlerMemmeletal.2019,
  author    = {Djuzenova, Cholpon S. and Fiedler, Vanessa and Memmel, Simon and Katzer, Astrid and Sisario, Dmitri and Brosch, Philippa K. and G{\"o}hrung, Alexander and Frister, Svenja and Zimmermann, Heiko and Flentje, Michael and Sukhorukov, Vladimir L.},
  title     = {Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells},
  series = {BMC Cancer},
  volume    = {19},
  journal   = {BMC Cancer},
  doi       = {10.1186/s12885-019-5517-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200290},
  pages     = {299},
  year      = {2019},
  abstract  = {Background Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells. Methods Using single-cell tracking and wound healing migration tests, colony-forming assay, Western blotting, flow cytometry and electrorotation we examined the effects of MK-2206 and PI-103 and/or irradiation on the migration, radiation sensitivity, expression of several marker proteins, DNA damage, cell cycle progression and the plasma membrane properties in two glioblastoma (DK-MG and SNB19) cell lines, previously shown to differ markedly in their migratory behavior and response to PI3K/mTOR inhibition. Results We found that MK-2206 strongly reduces the migration of DK-MG but only moderately reduces the migration of SNB19 cells. Surprisingly, MK-2206 did not cause radiosensitization, but even increased colony-forming ability after irradiation. Moreover, MK-2206 did not enhance the radiosensitizing effect of PI-103. The results appear to contradict the strong depletion of p-Akt in MK-2206-treated cells. Possible reasons for the radioresistance of MK-2206-treated cells could be unaltered or in case of SNB19 cells even increased levels of p-mTOR and p-S6, as compared to the reduced expression of these proteins in PI-103-treated samples. We also found that MK-2206 did not enhance IR-induced DNA damage, neither did it cause cell cycle distortion, nor apoptosis nor excessive autophagy. Conclusions Our study provides proof that MK-2206 can effectively inhibit the expression of Akt in two glioblastoma cell lines. However, due to an aberrant activation of mTOR in response to Akt inhibition in PTEN mutated cells, the therapeutic window needs to be carefully defined, or a combination of Akt and mTOR inhibitors should be considered.},
  language  = {en}
}
@phdthesis{Schmid2018,
  author    = {Schmid, Corinna},
  title     = {p53-Inaktivierung im Melanom - ein therapeutischer Ansatzpunkt?},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157853},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {Die Therapiem{\"o}glichkeiten f{\"u}r Patienten im Melanom Stadium IV sind nach wie vor begrenzt und die Erkrankung nur selten heilbar. Eine m{\"o}gliche Ziel¬struktur in der Melanom¬therapie der Zukunft k{\"o}nnte das im Melanom h{\"a}ufig genetisch wild¬typisch vorliegende p53 sein. F{\"u}r vorliegende Arbeit wurden humane Melanomzelllinien, welche stabil mit einem p53-Reportergenkonstrukt transduziert waren, hinsichtlich ihrer p53-Expression, -Akti-vit{\"a}t und -Akti¬vierbarkeit untersucht. Alle verwendeten Melanom¬zell¬¬¬linien exprimierten p53 un¬ab¬h{\"a}ngig vom p53-Mutations¬status. Drei der sieben untersuchten p53-wild¬typischen Melanomzelllinien zeigten keine oder nur sehr niedrige p53-Reporter¬gen¬aktivit{\"a}t. Die anderen vier p53-wildtypischen Zelllinien dagegen waren durch hohe, mittels p53-Knockdown unterdr{\"u}ckbare Reportergen¬expression gekennzeichnet. Die Proliferation dieser Zellen in Gegenwart von aktivem p53 belegt, dass Melanomzellen eine hohe Toleranz gegen{\"u}ber diesem Tumor¬suppressor besitzen k{\"o}nnen. Eine weitere Steige¬rung der p53-Expression und -Aktivit{\"a}t durch die Hemmung von MDM2 (mouse double minute 2) mit der Substanz Nutlin-3a f{\"u}hrte in den Zellen mit messbarer p53-Aktivit{\"a}t jedoch zu einem G1-Zell¬zyklusarrest. Dies belegt die prinzipielle Eignung von p53 als m{\"o}gliche thera¬peutische Zielstruktur. Aufgrund ihrer schlechten Biover¬f{\"u}g¬barkeit und hohen Toxizit{\"a}t gelten MDM2-Inhibitoren bisher aber als ungeeignet f{\"u}r den klinischen Einsatz. Die Reduktion hoher therapeutischer Nebenwirkungen k{\"o}nnte durch eine Melanom-spezifische Reaktivierung von p53 gelingen. Eine m{\"o}gliche negativ-modulierende Wirkung des Mela¬¬nom¬¬markers TRP2 (tyrosinase-related-protein 2) auf p53 wurde im Jahr 2010 von Sendoel et al. nach Unter¬suchungen am Fadenwurm C. elegans vorgeschlagen. TRP2 wird beim metastasierten Melanom in mehr als 80 \% der F{\"a}lle exprimiert und w{\"a}re, handelte es sich beim Melanom um einen weit verbreiteten Regulationsmechanismus, ein interessantes Zielprotein, um die Aktivit{\"a}t von p53 zu steigern. Die dargestellten Ergeb¬nisse zeigen, dass TRP2 zwar in vier von f{\"u}nf Melanomzelllinien exprimiert wurde, die Unterdr{\"u}ckung der TRP2-Expression jedoch weder spezifischen Einfluss auf die p53-Expression noch auf die p53-Reportergenaktivit{\"a}t zeigte. Auch das ver{\"a}nderte Wachs¬tums¬¬¬verhalten der Zellen nach Unterdr{\"u}ckung von TRP2 mittels drei unterschiedlicher shRNAs konnte im Rescue-Experiment, bei dem TRP nach seinem Knockdown ektop exprimiert wurde, keinem spezifischen Effekt von TRP2 auf die p53-Expression oder p53-Reporteraktivit{\"a}t zugeordnet werden. Auch in der TRP2-negativen Zelllinie f{\"u}hrte die ektope TRP2-Expression nicht zu einer verminderten p53-Expression oder -Aktivit{\"a}t. F{\"u}r das im Gegensatz zu MDM2 deutlich melanomspezifischere TRP2 konnte demensprechend kein sicherer regulatorischer Zusammenhang mit p53 dargestellt werden. Weitere Untersuchungen m{\"u}ssen zeigen, welche Bedeutung wildtypischem p53 im Melanom zukommt und ob sich weitere m{\"o}gliche p53-Regulatoren als therapeutische Angriffspunkte eignen.},
  subject      = {Melanom},
  language  = {de}
}
@article{KumarNaumannAigneretal.2015,
  author    = {Kumar, Praveen and Naumann, Ulrike and Aigner, Ludwig and Wischhusen, Joerg and Beier, Christoph P and Beier, Dagmar},
  title     = {Impaired TGF-β induced growth inhibition contributes to the increased proliferation rate of neural stem cells harboring mutant p53},
  series = {American Journal of Cancer Research},
  volume    = {5},
  journal   = {American Journal of Cancer Research},
  number    = {11},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144262},
  pages     = {3436-3445},
  year      = {2015},
  abstract  = {Gliomas have been classified according to their histological properties. However, their respective cells of origin are still unknown. Neural progenitor cells (NPC) from the subventricular zone (SVZ) can initiate tumors in murine models of glioma and are likely cells of origin in the human disease. In both, p53 signaling is often functionally impaired which may contribute to tumor formation. Also, TGF-beta, which under physiological conditions exerts a strong control on the proliferation of NPCs in the SVZ, is a potent mitogen on glioma cells. Here, we approach on the crosstalk between p53 and TGF-beta by loss of function experiments using NPCs derived from p53 mutant mice, as well as pharmacological inhibition of TGF-beta signaling using TGF-beta receptor inhibitors. NPC derived from p53 mutant mice showed increased clonogenicity and more rapid proliferation than their wildtype counterparts. Further, NPC derived from p53\(^{mut/mut}\) mice were insensitive to TGF-beta induced growth arrest. Still, the canonical TGF-beta signaling pathway remained functional in the absence of p53 signaling and expression of key proteins as well as phosphorylation and nuclear translocation of SMAD2 were unaltered. TGF-beta-induced p21 expression could, in contrast, only be detected in p53\(^{wt/wt}\) but not in p53\(^{mut/mut}\) NPC. Conversely, inhibition of TGF-beta signaling using SB431542 increased proliferation of p53\(^{wt/wt}\) but not of p53\(^{mut/mut}\) NPC. In conclusion, our data suggest that the TGF-beta induced growth arrest in NPC depends on functional p53. Mutational inactivation of p53 hence contributes to increased proliferation of NPC and likely to the formation of hyperplasia of the SVZ observed in p53 deficient mice in vivo.},
  language  = {en}
}