Browsing by Subject "GROWTH-FACTOR RECEPTOR"

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  • Sajanti, Antti; Lyne, Sean B.; Girard, Romuald; Frantzen, Janek; Rantamaki, Tomi; Heino, Iiro; Cao, Ying; Diniz, Cassiano; Umemori, Juzoh; Li, Yan; Takala, Riikka; Posti, Jussi P.; Roine, Susanna; Koskimäki, Fredrika; Rahi, Melissa; Rinne, Jaakko; Castren, Eero; Koskimäki, Janne (2020)
    P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR's related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n=235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (p
  • Koskensalo, Selja; Louhimo, Johanna; Hagström, Jaana; Lundin, Mikael; Stenman, Ulf Håkan; Haglund, Caj (2013)
  • Hellquist, Henrik; Ferlito, Alfio; Mäkitie, Antti A.; Thompson, Lester D. R.; Bishop, Justin A.; Agaimy, Abbas; Hernandez-Prera, Juan C.; Gnepp, Douglas R.; Willems, Stefan M.; Slootweg, Pieter J.; Rinaldo, Alessandra (2020)
    During the last 60 years numerous significant attempts have been made to achieve a widely acceptable terminology and histological grading for laryngeal squamous intraepithelial lesions. While dysplasia was included in the pathology of the uterine cervix already in 1953, the term dysplasia was accepted in laryngeal pathology first after the Toronto Centennial Conference on Laryngeal Cancer in 1974. In 1963 Kleinsasser proposed a three-tier classification, and in 1971 Kambic and Lenart proposed a four-tier classification. Since then, four editions of the World Health Organisation (WHO) classification have been proposed (1978, 1991, 2005 and 2017). Several terms such as squamous intraepithelial neoplasia (SIN) and laryngeal intraepithelial neoplasia (LIN) are now being abandoned and replaced by squamous intraepithelial lesions (SIL). The essential change between the 2005 and 2017 WHO classifications is the attempt to induce a simplification from a four- to a two-tier system. The current WHO classification (2017) thus recommends the use of a two-tier system with reasonably clear histopathological criteria for the two groups: low-grade and high-grade dysplasia. Problems with interobserver variability apart, subjectivities and uncertainties remain, but to a lesser degree. Ongoing and additional molecular studies may help to clarify underlying events that will increase our understanding and possibly can facilitate our attempts to obtain an even better classification. The classification needs to be easier for the general pathologist to perform and easier for the clinician to interpret. These two objectives are equally important to provide each patient the best personalised treatment available for squamous intraepithelial lesions.
  • Zhang, Linlin; Pradhan, Barun; Guo, Lili; Meng, Fanlu; Zhong, Diansheng (2020)
    Background Epidermal growth factor receptor (EGFR) activating mutations are usually associated with DNA damage repair (DDR) deficiency. However, the precise mechanism has remained elusive. In this study, we aimed to investigate whether EGFR exon 19 deletion mutation downstream signals contributed to DDR deficiency by downregulation of excision repair cross-complementation group-1 (ERCC1), a key factor in DDR, expression and function. Methods We first measured cell survival, DNA damage (gamma-H2AX foci formation) and damage repair (ERCC1 and RAD51 foci formation) ability in response to DNA cross-linking drug in EGFR exon 19 deletion and EGFR wild-type cells separately. We then investigated the involvement of EGFR downstream signals in regulating ERCC1 expression and function in EGFR exon 19 deletion cells as compared with EGFR wild-type ones. Results We observed increased gamma-H2AX, but impaired ERCC1 and RAD51 nuclear foci formation in EGFR exon 19 deletion cells as compared with EGFR wild-type ones treated with DNA cross-linker. In addition, we identified that inhibition of EGFR exon 19 deletion signals increased ERCC1 expression, whereas blocked wild-type EGFR signals decreased ERCC1 expression, on both mRNA and protein levels. Furthermore, EGFR exon 19 deletion downstream signals not only inhibited ERCC1 expression but also influenced ERCC1 foci formation in response to DNA cross-linker. Conclusion Our findings indicated that the aberrant EGFR exon 19 deletion signals were not only associated with decreased expression of ERCC1 but were also involved in impaired ERCC1 recruitment in response to DNA cross-link damage, thereby providing us with more evidence for exploring the mechanism of DDR deficiency in EGFR mutant NSCLC.
  • Aho, Joonas; Helenius, Mikko; Vattulainen-Collanus, Sanna; Alastalo, Tero-Pekka; Koskenvuo, Juha (2016)
    Cell damage can lead to rapid release of ATP to extracellular space resulting in dramatic change in local ATP concentration. Evolutionary, this has been considered as a danger signal leading to adaptive responses in adjacent cells. Our aim was to demonstrate that elevated extracellular ATP or inhibition of ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39) activity could be used to increase tolerance against DNA-damaging conditions. Human endothelial cells, with increased extracellular ATP concentration in cell proximity, were more resistant to irradiation or chemically induced DNA damage evaluated with the DNA damage markers gamma H2AX and phosphorylated p53. In our rat models of DNA damage, inhibiting CD39-driven ATP hydrolysis with POM-1 protected the heart and lung tissues against chemically induced DNA damage. Interestingly, the phenomenon could not be replicated in cancer cells. Our results show that transient increase in extracellular ATP can promote resistance to DNA damage.
  • Algars, Annika; Avoranta, Tuulia; Osterlund, Pia; Lintunen, Minnamaija; Sundstrom, Jari; Jokilehto, Terhi; Ristimaki, Ari; Ristamaki, Raija; Carpen, Olli (2014)
  • Greco, Dario; Kivi, Niina Johanna; Qian, Kui; Leivonen, Suvi-Katri Anneli; Auvinen, Petri Olli Viljami; Auvinen, Eeva (2011)
  • Ferone, Giustina; Thomason, Helen A.; Antonini, Dario; De Rosa, Laura; Hu, Bing; Gemei, Marica; Zhou, Huiqing; Ambrosio, Raffaele; Rice, David P.; Acampora, Dario; van Bokhoven, Hans; Del Vecchio, Luigi; Koster, Maranke I.; Tadini, Gianluca; Spencer-Dene, Bradley; Dixon, Michael; Dixon, Jill; Missero, Caterina (2012)
  • Cuppens, Tine; Annibali, Daniela; Coosemans, An; Trovik, Jone; ter Haar, Natalja; Colas, Eva; Garcia-Jimenez, Angel; Van de Vijver, Koen; Kruitwagen, Roy P. M.; Brinkhuis, Mariel; Zikan, Michal; Dundr, Pavel; Huvila, Jutta; Carpen, Olli; Haybaeck, Johannes; Moinfar, Farid; Salvesen, Helga B.; Stukan, Maciej; Mestdagh, Carole; Zweemer, Ronald P.; Massuger, Leonardus F.; Mallmann, Michael R.; Wardelmann, Eva; Mints, Miriam; Verbist, Godelieve; Thomas, Debby; Gomme, Ellen; Hermans, Els; Moerman, Philippe; Bosse, Tjalling; Amant, Frederic (2017)
    Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment. Experimental Design: We investigated the expression of several druggable targets (phospho-S6(S240) ribosomal protein, PTEN, PDGFR-alpha, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6(S240), was tested in patient-derived xenograft (PDX) leiomyosarcoma models. Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6(S240) correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6(S240) expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6(S240) in response prediction to PI3K/mTOR inhibition. Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6(S240) expression is a potential predictive biomarker for response to treatment. (C)2017 AACR.
  • Kleino, Iivari; Jarviluoma, Annika; Hepojoki, Jussi; Huovila, Ari Pekka; Saksela, Kalle (2015)
    A disintegrin and metalloproteinases (ADAMs) constitute a protein family essential for extracellular signaling and regulation of cell adhesion. Catalytic activity of ADAMs and their predicted potential for Src-homology 3 (SH3) domain binding show a strong correlation. Here we present a comprehensive characterization of SH3 binding capacity and preferences of the catalytically active ADAMs 8, 9, 10, 12, 15, 17, and 19. Our results revealed several novel interactions, and also confirmed many previously reported ones. Many of the identified SH3 interaction partners were shared by several ADAMs, whereas some were ADAM-specific. Most of the ADAM-interacting SH3 proteins were adapter proteins or kinases, typically associated with sorting and endocytosis. Novel SH3 interactions revealed in this study include TOCA1 and CIP4 as preferred partners of ADAM8, and RIMBP1 as a partner of ADAM19. Our results suggest that common as well as distinct mechanisms are involved in regulation and execution of ADAM signaling, and provide a useful framework for addressing the pathways that connect ADAMs to normal and aberrant cell behavior.
  • Pietilä, Mika; Sahgal, Pranshu; Peuhu, Emilia; Jäntti, Niklas Z.; Paatero, Ilkka; Närvä, Elisa; Al-Akhrass, Hussein; Lilja, Johanna; Georgiadou, Maria; Andersen, Olav M.; Padzik, Artur; Sihto, Harri; Joensuu, Heikki; Blomqvist, Matias; Saarinen, Irena; Boström, Peter J.; Taimen, Pekka; Ivaska, Johanna (2019)
    The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.
  • Kangaspeska, Sara; Hultsch, Susanne; Jaiswal, Alok; Edgren, Henrik; Mpindi, John-Patrick; Eldfors, Samuli; Bruck, Oscar; Aittokallio, Tero; Kallioniemi, Olli (2016)
    Background: The estrogen receptor (ER) inhibitor tamoxifen reduces breast cancer mortality by 31 % and has served as the standard treatment for ER-positive breast cancers for decades. However, 50 % of advanced ER-positive cancers display de novo resistance to tamoxifen, and acquired resistance evolves in 40 % of patients who initially respond. Mechanisms underlying resistance development remain poorly understood and new therapeutic opportunities are urgently needed. Here, we report the generation and characterization of seven tamoxifen-resistant breast cancer cell lines from four parental strains. Methods: Using high throughput drug sensitivity and resistance testing (DSRT) with 279 approved and investigational oncology drugs, exome-sequencing and network analysis, we for the first time, systematically determine the drug response profiles specific to tamoxifen resistance. Results: We discovered emerging vulnerabilities towards specific drugs, such as ERK1/2-, proteasome-and BCL-family inhibitors as the cells became tamoxifen-resistant. Co-resistance to other drugs such as the survivin inhibitor YM155 and the chemotherapeutic agent paclitaxel also occurred. Conclusion: This study indicates that multiple molecular mechanisms dictate endocrine resistance, resulting in unexpected vulnerabilities to initially ineffective drugs, as well as in emerging co-resistances. Thus, combatting drug-resistant tumors will require patient-tailored strategies in order to identify new drug vulnerabilities, and to understand the associated co-resistance patterns.
  • Capasso, Cristian; Garofalo, Mariangela; Hirvinen, Mari; Cerullo, Vincenzo (2014)