The Experts below are selected from a list of 7239 Experts worldwide ranked by ideXlab platform
Stefan Weiss - One of the best experts on this subject based on the ideXlab platform.
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the 37kda 67kda Laminin Receptor acts as a Receptor for aβ42 internalization
Scientific Reports, 2015Co-Authors: Bianca Da Costa Dias, Uwe Reusch, Stefan Knackmuss, Katarina Jovanovic, Danielle Gonsalves, Kiashanee Moodley, Marc S Weinberg, Melvyn Little, Stefan WeissAbstract:Neuronal loss is a major neuropathological hallmark of Alzheimer's disease (AD). The associations between soluble Aβ oligomers and cellular components cause this neurotoxicity. The 37 kDa/67 kDa Laminin Receptor (LRP/LR) has recently been implicated in Aβ pathogenesis. In this study the mechanism underlying the pathological role of LRP/LR was elucidated. Forsters Resonance Energy Transfer (FRET) revealed that LRP/LR and Aβ form a biologically relevant interaction. The ability of LRP/LR to form stable associations with endogenously shed Aβ was confirmed by pull down assays and Aβ-ELISAs. Antibody blockade of this association significantly lowered Aβ42 induced apoptosis. Furthermore, antibody blockade and shRNA mediated downregulation of LRP/LR significantly hampered Aβ42 internalization. These results suggest that LRP/LR is a Receptor for Aβ42 internalization, mediating its endocytosis and contributing to the cytotoxicity of the neuropeptide by facilitating intra-cellular Aβ42 accumulation. These findings recommend anti-LRP/LR specific antibodies and shRNAs as potential therapeutic tools for AD treatment.
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novel patented therapeutic approaches targeting the 37 67 kda Laminin Receptor for treatment of cancer and alzheimer s disease
Expert Opinion on Therapeutic Patents, 2015Co-Authors: Katarina Jovanovic, Carryn J. Chetty, Thandokuhle Khumalo, Bianca Da Costa Dias, Eloise Ferreira, Sibusiso T. Malindisa, Robert Caveney, Boitelo T. Letsolo, Stefan WeissAbstract:Introduction: The 37/67 kDa high-affinity Laminin Receptor (Laminin Receptor precursor/Laminin Receptor, LRP/LR) is a multi-faceted cellular Receptor. It plays a vital role in the malignancy of various cancer types where it is seen to contribute to invasion, adhesion, apoptosis evasion and angiogenesis. Furthermore, it has been found to play an important role in facilitating the processes leading to neurotoxicity in Alzheimer’s disease (AD). Various therapeutic options targeting this Receptor have been patented with the outlook on application for the treatment/prevention of these diseases.Areas covered: The various roles that LRP/LR plays in cancer, AD and infectious diseases caused by viruses and bacteria have been examined in detail and an overview of the current patented therapeutic strategies targeting this Receptor is given.Expert opinion: Molecular tools directed against LRP/LR, such as antibodies and small interfering RNA, could prove to be effective in the prevention of metastasis and angiogenesis...
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Novel patented therapeutic approaches targeting the 37/67 kDa Laminin Receptor for treatment of cancer and Alzheimer's disease.
Expert Opinion on Therapeutic Patents, 2015Co-Authors: Katarina Jovanovic, Carryn J. Chetty, Thandokuhle Khumalo, Bianca Da Costa Dias, Eloise Ferreira, Sibusiso T. Malindisa, Robert Caveney, Boitelo T. Letsolo, Stefan WeissAbstract:Introduction: The 37/67 kDa high-affinity Laminin Receptor (Laminin Receptor precursor/Laminin Receptor, LRP/LR) is a multi-faceted cellular Receptor. It plays a vital role in the malignancy of various cancer types where it is seen to contribute to invasion, adhesion, apoptosis evasion and angiogenesis. Furthermore, it has been found to play an important role in facilitating the processes leading to neurotoxicity in Alzheimer’s disease (AD). Various therapeutic options targeting this Receptor have been patented with the outlook on application for the treatment/prevention of these diseases.Areas covered: The various roles that LRP/LR plays in cancer, AD and infectious diseases caused by viruses and bacteria have been examined in detail and an overview of the current patented therapeutic strategies targeting this Receptor is given.Expert opinion: Molecular tools directed against LRP/LR, such as antibodies and small interfering RNA, could prove to be effective in the prevention of metastasis and angiogenesis...
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downregulation of the non integrin Laminin Receptor reduces cellular viability by inducing apoptosis in lung and cervical cancer cells
PLOS ONE, 2013Co-Authors: Kiashanee Moodley, Stefan WeissAbstract:The non-integrin Laminin Receptor, here designated the 37-kDa/67-kDa Laminin Receptor (LRP/LR), is involved in many physiologically relevant processes, as well as numerous pathological conditions. The overexpression of LRP/LR on various cancerous cell lines plays critical roles in tumour metastasis and angiogenesis. This study investigated whether LRP/LR is implicated in the maintenance of cellular viability in lung and cervical cancer cell lines. Here we show a significant reduction in cellular viability in the aforementioned cell lines as a result of the siRNA-mediated downregulation of LRP. This reduction in cellular viability is due to increased apoptotic processes, reflected by the loss of nuclear integrity and the significant increase in the activity of caspase-3. These results indicate that LRP/LR is involved in the maintenance of cellular viability in tumorigenic lung and cervix uteri cells through the blockage of apoptosis. Knockdown of LRP/LR by siRNA might represent an alternative therapeutic strategy for the treatment of lung and cervical cancer.
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patented biological approaches for the therapeutic modulation of the 37 kda 67 kda Laminin Receptor
Expert Opinion on Therapeutic Patents, 2011Co-Authors: Aadilah Omar, Katarina Jovanovic, Bianca Da Costa Dias, Robert Caveney, Danielle Gonsalves, Kiashanee Moodley, Vusi Mbazima, Stefan WeissAbstract:Importance of the field : The 37/67 kDa Laminin Receptor precursor/Laminin Receptor (LRP/LR) represents a multifunctional protein located on the cell surface, in the cytosol and the nucleus. The Receptor acts as a mediator for cell adhesion, cell proliferation and cell differentiation. It is a key player in invasion and adhesion, major functions of several important metastatic cancer types. The Receptor hampers apoptosis thereby favoring cancer progression. LRP/LR plays a major role as a cell surface Receptor in prion disorders and may be of considerable importance for other neurodegenerative diseases such as Alzheimer's disease. A series of viruses including Sindbis virus, Dengue virus and Adeno-associated virus use LRP/LR as attachment Receptors. Bacteria and Candida albicans use the Receptor for pathogenesis. Areas covered in this review: Background and patented biological approaches for therapeutic modulation of LRP/LR in neurodegenerative diseases, cancer, viral disorders, bacterial and yeast infecti...
James Varani - One of the best experts on this subject based on the ideXlab platform.
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abstract 2666 monoclonal antibodies specific for the oncofetal antigen immature Laminin Receptor tumor selectivity rapid internalization and in vivo efficacy
Cancer Research, 2014Co-Authors: Shannon D Mcclintock, Michael K Dame, Muhammad Aslam, Saqib Ali, Randall N Knibbs, Roscoe L Warner, James VaraniAbstract:A series of murine monoclonal antibodies were generated using recombinant oncofetal antigen - immature Laminin Receptor protein (OFA/iLRP) as the immunogen. Several of the antibodies detected the 37kD OFA/iLRP but did not recognize the structurally related 67kD mature Laminin Receptor protein (LRP), as determined by western blot analysis. Additional antibodies demonstrated reactivity with both proteins. Those antibodies specific for the 37kD moiety bound to recombinant OFA/iLRP with high affinity (K aff = 1-2 x 10 -10 M; Biacore technology). These antibodies also reacted with native OFA/iLRP on the surface of human tumor cells with high affinity (K aff = 1-2 x 10 -9 M) but did not show significant reactivity with normal human epithelial cells or fibroblasts. In contrast, antibodies that interacted with both 37kD OFA/iLRP and 67kD mature LRP were reactive with both tumor cells and normal cells. Antibodies specific to OFA/iLRP were internalized upon binding to the target protein on human tumor cells. Two monoclonal antibodies from this group were tested for anti-tumor activity in a murine model of B-cell leukemia. BALB/c mice were injected with A20 leukemia cells either intramuscularly or intravenously. Mice were given a total of six intraperitoneal 100µg antibody injections over a two-week period following tumor initiation. Both antibodies slowed growth of the intramuscular primary tumor by approximately 45%. More importantly, in the intravenous tumor model, the treatments reduced systemic blood tumor levels by greater than 70% and suppressed liver tumor formation by up to 46%. These high affinity tumor-selective antibodies potentially provide a front-line or adjuvant therapy for hematological malignancies. Citation Format: Shannon D. McClintock, Michael K. Dame, Muhammad N. Aslam, Saqib Ali, Randall N. Knibbs, Roscoe L. Warner, James Varani. Monoclonal antibodies specific for the oncofetal antigen - immature Laminin Receptor: Tumor selectivity, rapid internalization and in vivo efficacy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2666. doi:10.1158/1538-7445.AM2014-2666
Thomas Fröhlich - One of the best experts on this subject based on the ideXlab platform.
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invasion of tumorigenic ht1080 cells is impeded by blocking or downregulating the 37 kda 67 kda Laminin Receptor
Journal of Molecular Biology, 2008Co-Authors: Chantal Zuber, Georgeta Zemora, Uwe Reusch, Ekaterina Vlasova, Daniela Diehl, Vera Mick, Karin Hoffmann, Daphne Nikles, Stefan Knackmuss, Thomas FröhlichAbstract:The 37-kDa/67-kDa Laminin Receptor precursor/Laminin Receptor (LRP/LR) acting as a Receptor for prions and viruses is overexpressed in various cancer cell lines, and their metastatic potential correlates with LRP/LR levels. We analyzed the tumorigenic fibrosarcoma cell line HT1080 regarding 37-kDa/67-kDa LRP/LR levels and its invasive potential. Compared to the less invasive embryonic fibroblast cell line NIH3T3, the tumorigenic HT1080 cells display approximately 1.6-fold higher cell-surface levels of LRP/LR. We show that anti-LRP/LR tools interfere with the invasive potential of HT1080 cells. Anti-LRP/LR single-chain variable fragment antibody (scFv) iS18 generated by chain shuffling from parental scFv S18 and its full-length version immunoglobulin G1-iS18 reduced the invasive potential of HT1080 cells significantly by 37% and 38%, respectively. HT1080 cells transfected with lentiviral plasmids expressing small interfering RNAs directed against LRP mRNA showed reduced LRP levels by approximately 44%, concomitant with a significant decrease in the invasive potential by approximately 37%. The polysulfated glycans HM2602 and pentosan polysulfate (SP-54), both capable of blocking LRP/LR, reduced the invasive potential by 20% and 35%, respectively. Adhesion of HT1080 cells to Laminin-1 was significantly impeded by scFv iS18 and immunoglobulin G1-iS18 by 60% and 68%, respectively, and by SP-54 and HM2602 by 80%, suggesting that the reduced invasive capacity achieved by these tools is due to the perturbation of the LRP/LR–Laminin interaction on the cell surface. Our in vitro data suggest that reagents directed against LRP/LR or LRP mRNA such as antibodies, polysulfated glycans, or small interfering RNAs, previously shown to encompass an anti-prion activity by blocking or downregulating the prion Receptor LRP/LR, might also be potential cancer therapeutics blocking metastasis by interfering with the LRP/LR–Laminin interaction in neoplastic tissues.
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Invasion of Tumorigenic HT1080 Cells Is Impeded by Blocking or Downregulating the 37-kDa/67-kDa Laminin Receptor
Journal of Molecular Biology, 2008Co-Authors: Chantal Zuber, Georgeta Zemora, Uwe Reusch, Ekaterina Vlasova, Daniela Diehl, Vera Mick, Karin Hoffmann, Daphne Nikles, Stefan Knackmuss, Thomas FröhlichAbstract:The 37-kDa/67-kDa Laminin Receptor precursor/Laminin Receptor (LRP/LR) acting as a Receptor for prions and viruses is overexpressed in various cancer cell lines, and their metastatic potential correlates with LRP/LR levels. We analyzed the tumorigenic fibrosarcoma cell line HT1080 regarding 37-kDa/67-kDa LRP/LR levels and its invasive potential. Compared to the less invasive embryonic fibroblast cell line NIH3T3, the tumorigenic HT1080 cells display approximately 1.6-fold higher cell-surface levels of LRP/LR. We show that anti-LRP/LR tools interfere with the invasive potential of HT1080 cells. Anti-LRP/LR single-chain variable fragment antibody (scFv) iS18 generated by chain shuffling from parental scFv S18 and its full-length version immunoglobulin G1-iS18 reduced the invasive potential of HT1080 cells significantly by 37% and 38%, respectively. HT1080 cells transfected with lentiviral plasmids expressing small interfering RNAs directed against LRP mRNA showed reduced LRP levels by approximately 44%, concomitant with a significant decrease in the invasive potential by approximately 37%. The polysulfated glycans HM2602 and pentosan polysulfate (SP-54), both capable of blocking LRP/LR, reduced the invasive potential by 20% and 35%, respectively. Adhesion of HT1080 cells to Laminin-1 was significantly impeded by scFv iS18 and immunoglobulin G1-iS18 by 60% and 68%, respectively, and by SP-54 and HM2602 by 80%, suggesting that the reduced invasive capacity achieved by these tools is due to the perturbation of the LRP/LR–Laminin interaction on the cell surface. Our in vitro data suggest that reagents directed against LRP/LR or LRP mRNA such as antibodies, polysulfated glycans, or small interfering RNAs, previously shown to encompass an anti-prion activity by blocking or downregulating the prion Receptor LRP/LR, might also be potential cancer therapeutics blocking metastasis by interfering with the LRP/LR–Laminin interaction in neoplastic tissues.
Ameeq Ul Mushtaq - One of the best experts on this subject based on the ideXlab platform.
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characterization of the interaction between lysyl trna synthetase and Laminin Receptor by nmr
FEBS Letters, 2014Co-Authors: Hye Young Cho, Ameeq Ul Mushtaq, Jin Young Lee, Dae Gyu Kim, Min Sook Seok, Minseok Jang, Byung Woo Han, Sunghoon Kim, Young Ho JeonAbstract:Abstract Lysyl-tRNA synthetase (KRS) interacts with the Laminin Receptor (LR/RPSA) and enhances Laminin-induced cell migration in cancer metastasis. In this nuclear magnetic resonance (NMR)-based study, we show that the anticodon-binding domain of KRS binds directly to the C-terminal region of 37LRP, and the previously found inhibitors BC-K-01 and BC-K-YH16899 interfere with KRS–37LRP binding. In addition, the anticodon-binding domain of KRS binds to Laminin, observed by NMR and SPR. These results provide crucial insights into the structural characteristics of the KRS–LR interaction on the cell surface.
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chemical inhibition of prometastatic lysyl trna synthetase Laminin Receptor interaction
Nature Chemical Biology, 2014Co-Authors: Dae Gyu Kim, Hye Young Cho, Jin Young Lee, Nam Hoon Kwon, Pengfei Fang, Qian Zhang, Jing Wang, Nicolas L Young, Min Guo, Ameeq Ul MushtaqAbstract:Lysyl-tRNA synthetase (KRS), a protein synthesis enzyme in the cytosol, relocates to the plasma membrane after a Laminin signal and stabilizes a 67-kDa Laminin Receptor (67LR) that is implicated in cancer metastasis; however, its potential as an antimetastatic therapeutic target has not been explored. We found that the small compound BC-K-YH16899, which binds KRS, impinged on the interaction of KRS with 67LR and suppressed metastasis in three different mouse models. The compound inhibited the KRS-67LR interaction in two ways. First, it directly blocked the association between KRS and 67LR. Second, it suppressed the dynamic movement of the N-terminal extension of KRS and reduced membrane localization of KRS. However, it did not affect the catalytic activity of KRS. Our results suggest that specific modulation of a cancer-related KRS-67LR interaction may offer a way to control metastasis while avoiding the toxicities associated with inhibition of the normal functions of KRS.
Motofumi Kumazoe - One of the best experts on this subject based on the ideXlab platform.
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67-kDa Laminin Receptor Mediates the Beneficial Effects of Green Tea Polyphenol EGCG
Current Pharmacology Reports, 2020Co-Authors: Motofumi Kumazoe, Yoshinori Fujimura, Hirofumi TachibanaAbstract:Green tea is one of the most consumed beverages in the world. Through in vivo models and clinical trials, several studies have shown the beneficial effects of green tea. Epidemiological studies have revealed that green tea consumption is negatively correlated with the risk of cardiovascular diseases, stroke and cancer; however, little is known about the underlying molecular mechanisms. (−)-Epigallocatechin-3-O-gallate (EGCG) is one of the major bioactive compounds in green tea, and several studies emphasise its central role in the beneficial effects of green tea. It has been demonstrated that the 67-kDa Laminin Receptor, a non-integrin Laminin Receptor, mediates the beneficial effects of EGCG through cyclic guanosine monophosphate–dependent mechanisms. In this review, we showed the role of 67LR as the sensor of the EGCG and its downstream cascade, and this review provides the recent findings in the mechanism of the beneficial effect of EGCG.
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67-kDa Laminin Receptor Mediates the Beneficial Effects of Green Tea Polyphenol EGCG
Current Pharmacology Reports, 2020Co-Authors: Motofumi Kumazoe, Yoshinori Fujimura, Hirofumi TachibanaAbstract:Purpose of Review Green tea is one of the most consumed beverages in the world. Through in vivo models and clinical trials, several studies have shown the beneficial effects of green tea. Epidemiological studies have revealed that green tea consumption is negatively correlated with the risk of cardiovascular diseases, stroke and cancer; however, little is known about the underlying molecular mechanisms. Recent Findings (−)-Epigallocatechin-3- O -gallate (EGCG) is one of the major bioactive compounds in green tea, and several studies emphasise its central role in the beneficial effects of green tea. It has been demonstrated that the 67-kDa Laminin Receptor, a non-integrin Laminin Receptor, mediates the beneficial effects of EGCG through cyclic guanosine monophosphate–dependent mechanisms. Summary In this review, we showed the role of 67LR as the sensor of the EGCG and its downstream cascade, and this review provides the recent findings in the mechanism of the beneficial effect of EGCG.
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oligomer formation of a tea polyphenol egcg on its sensing molecule 67 kda Laminin Receptor
Chemical Communications, 2017Co-Authors: Yuhui Huang, Motofumi Kumazoe, Mami Sumida, Kaori Sugihara, Yumi Suemasu, Shuhei Yamada, Shuya Yamashita, Jyunichi Miyakawa, Takashi Takahashi, Hiroshi TanakaAbstract:Green tea polyphenol (−)-epigallocatechin-3-O-gallate (EGCG) has been attributed to the activation of its cell surface sensing Receptor 67 kDa Laminin Receptor (67LR). However, the action of EGCG to activate 67LR remains unknown. Here we show that EGCG undergoes oligomer formation on its surface Receptor 67LR.
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67 kda Laminin Receptor increases cgmp to induce cancer selective apoptosis
Journal of Clinical Investigation, 2013Co-Authors: Motofumi Kumazoe, Yuhui Huang, Kaori Sugihara, Yumi Suemasu, Shuya Yamashita, Shuntaro Tsukamoto, Yukari Tsurudome, Takashi Suzuki, Naoki Ueda, Yoon Hee KimAbstract:The 67-kDa Laminin Receptor (67LR) is a Laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death Receptor. In this cell death Receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCδ/acid sphingomyelinase (PKCδ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (–)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.
