Moll, Ute M.

[["dc.bibliographiccitation.firstpage","275"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Journal of Experimental Medicine"],["dc.bibliographiccitation.lastpage","289"],["dc.bibliographiccitation.volume","209"],["dc.contributor.author","Schulz, Ramona"],["dc.contributor.author","Marchenko, Natalia D."],["dc.contributor.author","Holembowski, Lena"],["dc.contributor.author","Fingerle-Rowson, Guenter"],["dc.contributor.author","Pesic, Marina"],["dc.contributor.author","Zender, Lars"],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T09:13:28Z"],["dc.date.available","2018-11-07T09:13:28Z"],["dc.date.issued","2012"],["dc.description.abstract","Intracellular macrophage migration inhibitory factor (MIF) often becomes stabilized in human cancer cells. MIF can promote tumor cell survival, and elevated MIF protein correlates with tumor aggressiveness and poor prognosis. However, the molecular mechanism facilitating MIF stabilization in tumors is not understood. We show that the tumor-activated HSP90 chaperone complex protects MIF from degradation. Pharmacological inhibition of HSP90 activity, or siRNA-mediated knockdown of HSP90 or HDAC6, destabilizes MIF in a variety of human cancer cells. The HSP90-associated E3 ubiquitin ligase CHIP mediates the ensuing proteasome-dependent MIF degradation. Cancer cells contain constitutive endogenous MIF-HSP90 complexes. siRNA-mediated MIF knockdown inhibits proliferation and triggers apoptosis of cultured human cancer cells, whereas HSP90 inhibitor-induced apoptosis is overridden by ectopic MIF expression. In the ErbB2 transgenic model of human HER2-positive breast cancer, genetic ablation of MIF delays tumor progression and prolongs overall survival of mice. Systemic treatment with the HSP90 inhibitor 17AAG reduces MIF expression and blocks growth of MIF-expressing, but not MIF-deficient, tumors. Together, these findings identify MIF as a novel HSP90 client and suggest that HSP90 inhibitors inhibit ErbB2-driven breast tumor growth at least in part by destabilizing MIF."],["dc.identifier.doi","10.1084/jem.20111117"],["dc.identifier.isi","000301943200009"],["dc.identifier.pmid","22271573"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10625"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/27181"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Rockefeller Univ Press"],["dc.relation.issn","0022-1007"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1411"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Landmann, H."],["dc.contributor.author","Proia, D. A."],["dc.contributor.author","He, S."],["dc.contributor.author","Ogden, F. L."],["dc.contributor.author","Kramer, Franz-Josef"],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Grade, Marian"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Moll, U."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T09:35:41Z"],["dc.date.available","2018-11-07T09:35:41Z"],["dc.date.issued","2014"],["dc.description.abstract","HSP90 inhibition represents a promising route to cancer therapy, taking advantage of cancer cell-inherent proteotoxic stress. The HSP90-inhibitor ganetespib showed benefit in advanced clinical trials. This raises the need to identify the molecular determinants of treatment response. We tested the efficacy of ganetespib on a series of colorectal cancer (CRC)-derived cell lines and correlated their sensitivities with comprehensive gene expression analysis. Notably, the drug concentration required for 50% growth inhibition (IC50) varied up to 70-fold (from 36 to 2500 nM) between different cell lines. Correlating cell line-specific IC(50)s with the corresponding gene expression patterns revealed a strong association between ganetespib resistance (IC50 > 500 nM) and high expression of the UDP glucuronosyltransferase 1A (UGT1A) gene cluster. Moreover, CRC tumor samples showed a comparable distribution of UGT1A expression levels. The members of the UGT1A gene family are known as drug-conjugating liver enzymes involved in drug excretion, but their function in tumor cells is hardly understood. Chemically unrelated HSP90 inhibitors, for example, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), did not show correlation of drug sensitivities with UGT1A levels, whereas the ganetespib-related compound NVP-AUY922 did. When the most ganetespib-resistant cell line, HT29, was treated with ganetespib, the levels of HSP90 clients were unaffected. However, HT29 cells became sensitized to the drug, and HSP90 client proteins were destabilized by ganetespib upon siRNA-mediated UGT1A knockdown. Conversely, the most ganetespib-sensitive cell lines HCT116 and SW480 became more tolerant toward ganetespib upon UGT1A overexpression. Mechanistically, ganetespib was rapidly glucuronidated and excreted in resistant but not in sensitive CRC lines. We conclude that CRC cell-expressed UGT1A inactivates ganetespib and other resorcinolic Hsp90 inhibitors by glucuronidation, which renders the drugs unable to inhibit Hsp90 and thereby abrogates their biological activity. UGT1A levels in tumor tissues may be a suitable predictive biomarker to stratify CRC patients for ganetespib treatment."],["dc.description.sponsorship","Open-Access Publikationsfonds 2014"],["dc.identifier.doi","10.1038/cddis.2014.378"],["dc.identifier.isi","000343162000012"],["dc.identifier.pmid","25210794"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10891"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/32445"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY-NC-ND 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/3.0"],["dc.title","UDP glucuronosyltransferase 1A expression levels determine the response of colorectal cancer cells to the heat shock protein 90 inhibitor ganetespib"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","10094"],["dc.bibliographiccitation.issue","24"],["dc.bibliographiccitation.journal","Cancer Research"],["dc.bibliographiccitation.lastpage","10104"],["dc.bibliographiccitation.volume","68"],["dc.contributor.author","Braun, Christian J."],["dc.contributor.author","Zhang, X."],["dc.contributor.author","Savelyeva, Irina"],["dc.contributor.author","Wolff, Sonja"],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Schepeler, Troels"],["dc.contributor.author","Orntoft, Torben F."],["dc.contributor.author","Andersen, Claus L."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.date.accessioned","2018-11-07T11:07:54Z"],["dc.date.available","2018-11-07T11:07:54Z"],["dc.date.issued","2008"],["dc.description.abstract","microRNAs provide a novel layer of regulation for gene expression by interfering with the stability and/or translation of specific target mRNAs. Overall levels of microRNTAs are frequently down-regulated in cancer cells, and reducing general microRNA processing increases cancerogenesis in transgenic models, suggesting that at least some microRNAs might act as effectors in tumor suppression. Accordingly, the tumor suppressor p53 up-regulates miR-34a, a microR-NtA that contributes to apoptosis and acute senescence. Here, we used array hybridization to rind that p53 induces two additional, mutually related clusters of microRNAs, leading to the up-regulation of miR-192, miR-194, and miR-215. The same microRNAs were detected at high levels in normal colon tissue but were severely reduced in many colon cancer samples. On the other hand, miR-192 and its cousin miR-215 can each contribute to enhanced CDKN1A/p21 levels, colony suppression, cell cycle arrest, and cell detachment from a solid support. These effects were partially dependent on the presence of wild-type p53. Antagonizing endogenous miR-192 attenuated 5-fluorouracil-induced accumulation of p21. Hence, miR-192 and miR-215 can act as effectors as well as regulators of p53; they seem to suppress cancerogenesis through p21 accumulation and cell cycle arrest. [Cancer Res 2008;68(24):10094-104]"],["dc.description.sponsorship","NCI NIH HHS [R01 CA060664, R01 CA060664-13]"],["dc.identifier.doi","10.1158/0008-5472.CAN-08-1569"],["dc.identifier.isi","000261866800013"],["dc.identifier.pmid","19074875"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6279"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/52681"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Assoc Cancer Research"],["dc.relation.issn","0008-5472"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","p53-Responsive MicroRNAs 192 and 215 Are Capable of Inducing Cell Cycle Arrest"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e2661"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Alexandrova, Evguenia M."],["dc.contributor.author","Mirza, Safia A."],["dc.contributor.author","Xu, S."],["dc.contributor.author","Schulz-Heddergott, Ramona"],["dc.contributor.author","Marchenko, Natalia D."],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T10:26:40Z"],["dc.date.available","2018-11-07T10:26:40Z"],["dc.date.issued","2017"],["dc.description.abstract","Missense mutations in TP53 comprise > 75% of all p53 alterations in cancer, resulting in highly stabilized mutant p53 proteins that not only lose their tumor-suppressor activity, but often acquire oncogenic gain-of-functions (GOFs). GOF manifests itself in accelerated tumor onset, increased metastasis, increased drug resistance and shortened survival in patients and mice. A known prerequisite for GOF is mutant p53 protein stabilization, which itself is linked to aberrant protein conformation. However, additional determinants for mutant p53 stabilization likely exist. Here we show that in initially heterozygous mouse tumors carrying the hotspot GOF allele R248Q (p53Q/+), another necessary prerequisite for mutant p53 stabilization and GOF in vivo is loss of the remaining wild-type p53 allele, termed loss-of-heterozygosity (LOH). Thus, in mouse tumors with high frequency of p53 LOH (osteosarcomas and fibrosarcomas), we find that mutant p53 protein is stabilized (16/17 cases, 94%) and tumor onset is significantly accelerated compared with p53+/- tumors (GOF). In contrast, in mouse tumors with low frequency of p53 LOH (MMTV-Neu breast carcinomas), mutant p53 protein is not stabilized (16/20 cases, 80%) and GOF is not observed. Of note, human genomic databases (TCGA, METABRIC etc.) show a high degree of p53 LOH in all examined tumor types that carry missense p53 mutations, including sarcomas and breast carcinomas (with and without HER2 amplification). These data - while cautioning that not all genetic mouse models faithfully represent the human situation - demonstrate for the first time that p53 LOH is a critical prerequisite for missense mutant p53 stabilization and GOF in vivo."],["dc.identifier.doi","10.1038/cddis.2017.80"],["dc.identifier.isi","000397447100026"],["dc.identifier.pmid","28277540"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14951"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43090"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","p53 loss-of-heterozygosity is a necessary prerequisite for mutant p53 stabilization and gain-of-function in vivo"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e980"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Schulz, R."],["dc.contributor.author","Streller, F."],["dc.contributor.author","Scheel, Andreas Hans"],["dc.contributor.author","Rueschoff, Josef"],["dc.contributor.author","Reinert, M. C."],["dc.contributor.author","Dobbelstein, Matthias"],["dc.contributor.author","Marchenko, N. D."],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T09:46:24Z"],["dc.date.available","2018-11-07T09:46:24Z"],["dc.date.issued","2014"],["dc.description.abstract","Overexpression of the human epidermal growth factor receptor-2 (HER2) in breast cancer strongly correlates with aggressive tumors and poor prognosis. Recently, a positive correlation between HER2 and MIF (macrophage migration inhibitory factor, a tumor-promoting protein and heat-shock protein 90 (HSP90) client) protein levels was shown in cancer cells. However, the underlying mechanistic link remained unknown. Here we show that overexpressed HER2 constitutively activates heat-shock factor 1 (HSF1), the master transcriptional regulator of the inducible proteotoxic stress response of heat-shock chaperones, including HSP90, and a crucial factor in initiation and maintenance of the malignant state. Inhibiting HER2 pharmacologically by Lapatinib (a dual HER2/epidermal growth factor receptor inhibitor) or CP724.714 (a specific HER2 inhibitor), or by knockdown via siRNA leads to inhibition of phosphoactivated Ser326 HSF1, and subsequently blocks the activity of the HSP90 chaperone machinery in HER2-overexpressing breast cancer lines. Consequently, HSP90 clients, including MIF, AKT, mutant p53 and HSF1 itself, become destabilized, which in turn inhibits tumor proliferation. Mechanistically, HER2 signals via the phosphoinositide-3kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis to induce activated pSer326 HSF1. Heat-shock stress experiments confirm this functional link between HER2 and HSF1, as HER2 (and PI3K) inhibition attenuate the HSF1-mediated heat-shock response. Importantly, we confirmed this axis in vivo. In the mouse model of HER2-driven breast cancer, ErbB2 inhibition by Lapatinib strongly suppresses tumor progression, and this is associated with inactivation of the HSF1 pathway. Moreover, ErbB2-overexpressing cancer cells derived from a primary mouse ErbB2 tumor also show HSF1 inactivation and HSP90 client destabilization in response to ErbB2 inhibition. Furthermore, in HER2-positive human breast cancers HER2 levels strongly correlate with pSer326 HSF1 activity. Our results show for the first time that HER2/ErbB2 overexpression controls HSF1 activity, with subsequent stabilization of numerous tumor-promoting HSP90 clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2014"],["dc.identifier.doi","10.1038/cddis.2013.508"],["dc.identifier.isi","000332222700004"],["dc.identifier.pmid","24384723"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/9556"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34861"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY-NC-SA 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-sa/3.0"],["dc.title","HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Cancers"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Schulz-Heddergott, Ramona"],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2019-07-09T11:45:42Z"],["dc.date.available","2019-07-09T11:45:42Z"],["dc.date.issued","2018"],["dc.description.abstract","p53 missense mutant alleles are present in nearly 40% of all human tumors. Such mutated alleles generate aberrant proteins that not only lose their tumor-suppressive functions but also frequently act as driver oncogenes, which promote malignant progression, invasion, metastasis, and chemoresistance, leading to reduced survival in patients and mice. Notably, these oncogenic gain-of-function (GOF) missense mutant p53 proteins (mutp53) are constitutively and tumor-specific stabilised. This stabilisation is one key pre-requisite for their GOF and is largely due to mutp53 protection from the E3 ubiquitin ligases Mdm2 and CHIP by the HSP90/HDAC6 chaperone machinery. Recent mouse models provide convincing evidence that tumors with highly stabilized GOF mutp53 proteins depend on them for growth, maintenance, and metastasis, thus creating exploitable tumor-specific vulnerabilities that markedly increase lifespan if intercepted. This identifies mutp53 as a promising cancer-specific drug target. This review discusses direct mutp53 protein-targeting drug strategies that are currently being developed at various preclinical levels."],["dc.identifier.doi","10.3390/cancers10060188"],["dc.identifier.pmid","29875343"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15288"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59288"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","MDPI"],["dc.relation.eissn","2072-6694"],["dc.relation.issn","2072-6694"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","300"],["dc.subject.ddc","320"],["dc.title","Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2070"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Journal of Clinical Investigation"],["dc.bibliographiccitation.lastpage","2080"],["dc.bibliographiccitation.volume","120"],["dc.contributor.author","Nemajerova, Alice"],["dc.contributor.author","Petrenko, Oleksi"],["dc.contributor.author","Truemper, Lorenz H."],["dc.contributor.author","Palacios, Gustavo"],["dc.contributor.author","Moll, Ute M."],["dc.date.accessioned","2018-11-07T08:42:48Z"],["dc.date.available","2018-11-07T08:42:48Z"],["dc.date.issued","2010"],["dc.description.abstract","Mice engineered to express c-Myc in B cells (E mu-myc mice) develop lethal lymphomas in which the gene encoding the p53 tumor suppressor is frequently mutated. Whether the p53 homolog p73 also functions as a tumor suppressor in vivo remains controversial. Here we have shown that p73 loss does not substantially affect disease onset and mortality in E mu-myc mice. However, it does alter the phenotype of the disease. Specifically, p73 loss decreased nodal disease and increased widespread extranocial dissemination. We further found that p53 acted as the dominant tumor suppressor during the onset of E mu-myc-driven B cell lymphomagenesis, while p73 modulated tumor dissemination and extranodal growth. Immunophenotyping and expression profiling suggested that p73 loss allowed increased maturation of malignant B cells and deregulated genes involved in lymphocyte homing and dissemination of human lymphomas. Consistent with this, p73 expression was frequently downregulated in a large cohort of human mature aggressive B cell lymphomas, and both the incidence and degree of p73 downregulation in these tumors correlated with their extranodal dissemination status. These data indicate that p73 is a modifier of Myc-driven lymphomas in mice, favoring tumor dissemination, and suggest that p73 could be a biomarker for human B cell lymphoma dissemination, a notion that can now be tested in clinicopathologic correlation studies."],["dc.identifier.doi","10.1172/JCI40331"],["dc.identifier.isi","000278324400030"],["dc.identifier.pmid","20484818"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/7565"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19786"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Soc Clinical Investigation Inc"],["dc.relation.issn","0021-9738"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Loss of p73 promotes dissemination of Myc-induced B cell lymphomas in mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","4019"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Isermann, Tamara"],["dc.contributor.author","Şener, Özge Çiçek"],["dc.contributor.author","Stender, Adrian"],["dc.contributor.author","Klemke, Luisa"],["dc.contributor.author","Winkler, Nadine"],["dc.contributor.author","Neesse, Albrecht"],["dc.contributor.author","Li, Jinyu"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Schulz-Heddergott, Ramona"],["dc.date.accessioned","2021-08-12T07:44:56Z"],["dc.date.available","2021-08-12T07:44:56Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract The vast majority of human tumors with p53 mutations undergo loss of the remaining wildtype p53 allele (loss-of-heterozygosity, p53LOH). p53LOH has watershed significance in promoting tumor progression. However, driving forces for p53LOH are poorly understood. Here we identify the repressive WTp53–HSF1 axis as one driver of p53LOH. We find that the WTp53 allele in AOM/DSS chemically-induced colorectal tumors (CRC) of p53 R248Q/+ mice retains partial activity and represses heat-shock factor 1 (HSF1), the master regulator of the proteotoxic stress response (HSR) that is ubiquitously activated in cancer. HSR is critical for stabilizing oncogenic proteins including mutp53. WTp53-retaining CRC tumors, tumor-derived organoids and human CRC cells all suppress the tumor-promoting HSF1 program. Mechanistically, retained WTp53 activates CDKN1A /p21, causing cell cycle inhibition and suppression of E2F target MLK3. MLK3 links cell cycle with the MAPK stress pathway to activate the HSR response. In p53 R248Q/+ tumors WTp53 activation by constitutive stress represses MLK3, thereby weakening the MAPK-HSF1 response necessary for tumor survival. This creates selection pressure for p53LOH which eliminates the repressive WTp53-MAPK-HSF1 axis and unleashes tumor-promoting HSF1 functions, inducing mutp53 stabilization enabling invasion."],["dc.description.sponsorship","Open-Access-Finanzierung durch die Universitätsmedizin Göttingen 2021"],["dc.identifier.doi","10.1038/s41467-021-24064-1"],["dc.identifier.pii","24064"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88334"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-448"],["dc.relation.eissn","2041-1723"],["dc.rights","CC BY 4.0"],["dc.title","Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Oncology"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Klemke, Luisa"],["dc.contributor.author","Fehlau, Clara F."],["dc.contributor.author","Winkler, Nadine"],["dc.contributor.author","Toboll, Felicia"],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Schulz-Heddergott, Ramona"],["dc.date.accessioned","2021-08-12T07:45:46Z"],["dc.date.available","2021-08-12T07:45:46Z"],["dc.date.issued","2021"],["dc.description.abstract","Missense p53 mutations (mutp53) occur in approx. 70% of pancreatic ductal adenocarcinomas (PDAC). Typically, mutp53 proteins are aberrantly stabilized by Hsp90/Hsp70/Hsp40 chaperone complexes. Notably, stabilization is a precondition for specific mutp53 alleles to acquire powerful neomorphic oncogenic gain-of-functions (GOFs) that promote tumor progression in solid cancers mainly by increasing invasion and metastasis. In colorectal cancer (CRC), we recently established that the common hotspot mutants mutp53 R248Q and mutp53 R248W exert GOF activities by constitutively binding to and hyperactivating STAT3. This results in increased proliferation and invasion in an autochthonous CRC mouse model and correlates with poor survival in patients. Comparing a panel of p53 missense mutations in a series of homozygous human PDAC cell lines, we show here that, similar to CRC, the mutp53 R248W protein again undergoes a strong Hsp90-mediated stabilization and selectively promotes migration. Highly stabilized mutp53 is degradable by the Hsp90 inhibitors Onalespib and Ganetespib, and correlates with growth suppression, possibly suggesting therapeutic vulnerabilities to target GOF mutp53 proteins in PDAC. In response to mutp53 depletion, only mutp53 R248W harboring PDAC cells show STAT3 de-phosphorylation and reduced migration, again suggesting an allele-specific GOF in this cancer entity, similar to CRC. Moreover, mutp53 R248W also exhibits the strongest constitutive complex formation with phosphorylated STAT3. The selective mutp53 R248W GOF signals through enhancing the STAT3 axis, which was confirmed since targeting STAT3 by knockdown or pharmacological inhibition phenocopied mutp53 depletion and reduced cell viability and migration preferentially in mutp53 R248W -containing PDAC cells. Our results confirm that mutp53 GOF activities are allele specific and can span across tumor entities."],["dc.description.abstract","Missense p53 mutations (mutp53) occur in approx. 70% of pancreatic ductal adenocarcinomas (PDAC). Typically, mutp53 proteins are aberrantly stabilized by Hsp90/Hsp70/Hsp40 chaperone complexes. Notably, stabilization is a precondition for specific mutp53 alleles to acquire powerful neomorphic oncogenic gain-of-functions (GOFs) that promote tumor progression in solid cancers mainly by increasing invasion and metastasis. In colorectal cancer (CRC), we recently established that the common hotspot mutants mutp53 R248Q and mutp53 R248W exert GOF activities by constitutively binding to and hyperactivating STAT3. This results in increased proliferation and invasion in an autochthonous CRC mouse model and correlates with poor survival in patients. Comparing a panel of p53 missense mutations in a series of homozygous human PDAC cell lines, we show here that, similar to CRC, the mutp53 R248W protein again undergoes a strong Hsp90-mediated stabilization and selectively promotes migration. Highly stabilized mutp53 is degradable by the Hsp90 inhibitors Onalespib and Ganetespib, and correlates with growth suppression, possibly suggesting therapeutic vulnerabilities to target GOF mutp53 proteins in PDAC. In response to mutp53 depletion, only mutp53 R248W harboring PDAC cells show STAT3 de-phosphorylation and reduced migration, again suggesting an allele-specific GOF in this cancer entity, similar to CRC. Moreover, mutp53 R248W also exhibits the strongest constitutive complex formation with phosphorylated STAT3. The selective mutp53 R248W GOF signals through enhancing the STAT3 axis, which was confirmed since targeting STAT3 by knockdown or pharmacological inhibition phenocopied mutp53 depletion and reduced cell viability and migration preferentially in mutp53 R248W -containing PDAC cells. Our results confirm that mutp53 GOF activities are allele specific and can span across tumor entities."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.3389/fonc.2021.642603"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88548"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-448"],["dc.relation.eissn","2234-943X"],["dc.relation.orgunit","Institut für Molekulare Onkologie"],["dc.rights","CC BY 4.0"],["dc.title","The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]