ORCID Profile
0000-0002-1186-6390
Current Organisation
University of California, San Diego
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Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.BBCAN.2017.09.002
Abstract: The initial experiments performed by Rose, Hershko, and Ciechanover describing the identification of a specific degradation signal in short-lived proteins paved the way to the discovery of the ubiquitin mediated regulation of numerous physiological functions required for cellular homeostasis. Since their discovery of ubiquitin and ubiquitin function over 30years ago it has become wholly apparent that ubiquitin and their respective ubiquitin modifying enzymes are key players in tumorigenesis. The human genome encodes approximately 600 putative E3 ligases and 80 deubiquitinating enzymes and in the majority of cases these enzymes exhibit specificity in sustaining either pro-tumorigenic or tumour repressive responses. In this review, we highlight the known oncogenic and tumour suppressive effects of ubiquitin modifying enzymes in cancer relevant pathways with specific focus on PI3K, MAPK, TGFβ, WNT, and YAP pathways. Moreover, we discuss the capacity of targeting DUBs as a novel anticancer therapeutic strategy.
Publisher: Impact Journals, LLC
Date: 28-02-2018
Publisher: Springer Science and Business Media LLC
Date: 24-08-2022
DOI: 10.1186/S13046-022-02425-Y
Abstract: Pancreatic cancer is one of the most difficult cancers to detect early and most patients die from complications arising due to distant organ metastases. The lack of bona fide early biomarkers is one of the primary reasons for late diagnosis of pancreatic cancer. It is a multifactorial disease and warrants a novel approach to identify early biomarkers. In order to characterize the proteome, Extracellular vesicles (EVs) isolated from different in vitro conditions mimicking tumor-microenvironment interactions between pancreatic cancer epithelial and stromal cells were analyzed using high throughput mass spectrometry. The biological activity of the secreted EVome was analyzed by investigating changes in distant organ metastases and associated early changes in the microbiome. Candidate biomarkers (KIF5B, SFRP2, LOXL2, and MMP3) were selected and validated on a mouse-human hybrid Tissue Microarray (TMA) that was specifically generated for this study. Additionally, a human TMA was used to analyze the expression of KIF5B and SFRP2 in progressive stages of pancreatic cancer. The EVome of co-cultured epithelial and stromal cells is different from in idual cells with distinct protein compositions. EVs secreted from stromal and cancer cells cultures could not induce significant changes in Pre-Metastatic Niche (PMN) modulation, which was assessed by changes in the distant organ metastases. However, they did induce significant changes in the early microbiome, as indicated by differences in α and β- ersities. KIF5B and SFRP2 show promise for early detection and investigation in progressive pancreatic cancer. These markers are expressed in all stages of pancreatic cancer such as low grade PanINs, advanced cancer, and in liver and soft tissue metastases. Proteomic characterization of EVs derived from mimicking conditions of epithelial and stromal cells in the tumor-microenvironment resulted in the identification of several proteins, some for the first time in EVs. These secreted EVs cannot induce changes in distant organ metastases in in vivo models of EV education, but modulate changes in the early murine microbiome. Among all the proteins that were analyzed (MMP3, KIF5B, SFRP2, and LOXL2), KIF5B and SFRP2 show promise as bona fide early pancreatic cancer biomarkers expressed in progressive stages of pancreatic cancer.
Publisher: Springer International Publishing
Date: 2016
DOI: 10.1007/82_2015_443
Abstract: Balanced gene expression is a high priority in order to maintain optimal functioning since alterations and variations could result in acute consequences. X chromosome inactivation (X-inactivation) is one such strategy utilized by mammalian species to silence the extra X chromosome in females to uphold a similar level of expression between the two sexes. A functionally versatile class of molecules called long noncoding RNA (lncRNA) has emerged as key regulators of gene expression and plays important roles during development. An lncRNA that is indispensable for X-inactivation is X-inactive specific transcript (Xist), which induces a repressive epigenetic landscape and creates the inactive X chromosome (Xi). With recent advents in the field of X-inactivation, novel positive and negative lncRNA regulators of Xist such as Jpx and Tsix, respectively, have broadened the regulatory network of X-inactivation. Xist expression failure or dysregulation has been implicated in producing developmental anomalies and disease states. Subsequently, reactivation of the Xi at a later stage of development has also been associated with certain tumors. With the recent influx of information about lncRNA biology and advancements in methods to probe lncRNA, we can now attempt to understand this complex network of Xist regulation in development and disease. It has become clear that the presence of an extra set of genes could be fatal for the organism. Only by understanding the precise ways in which lncRNAs function can treatments be developed to bring aberrations under control. This chapter summarizes our current understanding and knowledge with regard to how lncRNAs are orchestrated at the X-inactivation center (Xic), with a special focus on how genetic diseases come about as a consequence of lncRNA dysregulation.
Publisher: Public Library of Science (PLoS)
Date: 26-09-2013
Publisher: Oxford University Press (OUP)
Date: 10-07-2018
DOI: 10.1093/NAR/GKY615
Publisher: Elsevier BV
Date: 12-2018
Publisher: Oxford University Press (OUP)
Date: 03-12-2010
DOI: 10.1093/NAR/GKQ1174
Publisher: Springer Science and Business Media LLC
Date: 16-10-2023
Publisher: MDPI AG
Date: 31-05-2021
Abstract: Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tumor cells, CTCs) either alone or as tumor microemboli (clusters) the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell–cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tissue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on companion cells in clusters.
Publisher: MyJove Corporation
Date: 26-11-2014
DOI: 10.3791/52053
Publisher: Rockefeller University Press
Date: 07-06-2018
DOI: 10.1084/JEM.20171960
Abstract: RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.
Publisher: Springer Science and Business Media LLC
Date: 29-05-2018
Publisher: Elsevier BV
Date: 2016
Publisher: Public Library of Science (PLoS)
Date: 07-07-2017
Location: India
Location: Singapore
Location: United States of America
No related grants have been discovered for John Lalith Charles Richard.