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Pathogenesis: Molecular mechanisms of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Anastasia E. Markatseli, Theodora E. Markatseli, Alexandros A. Drosos
RANKL binds to the osteoclast cell-surface receptor RANK. Subsequently, RANK is trimerized and recruits a member of the TNF receptor-associated factors (TRAFs) at specific sites within its cytoplasmic domain (167). These factors are TRAF 2, 5, and 6. The most basic factor for osteoclasts (precursors and mature) seems to be TRAF 6 (56,168). The signaling pathways that are activated after the binding of RANK with TRAF are as follows: Four pathways that induce the formation of osteoclasts: (a) inhibitor of NF-κB kinase (IKK)/NF-κB), (b) nuclear factor of activated T cells (NFATc1), (c) c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1), and (d) c-myc.Three pathways that mediate activation ([a] MKK6/p38/MITF and [b] Src) and survival of osteoclasts ([a] kinase pathway regulated by extracellular signal and [b] Src pathway) (169). Figure 2.2a summarizes the signal transduction pathways after RANK.
Melanin
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
M. Badawy Abdel-Naser, Sabine Krueger-Krasagakis, Konstantinos Krasagakis
It has been shown that loss-of-function mutations of the MITF gene cause Waardenburg syndrome type 2 (WS2),82 whereas a dominant negative mutation of MITF causes Tiez syndrome, i.e., albinism–deafness syndrome, whose symptoms are similar to WS2 but more severe.83,84 In both syndromes, MITF mutations often cause hearing impairment, along with skin and iris pigmentation anomalies. Both the pigmentation anomaly and the hearing impairment are caused by the absence of melanocytes.76 On the other hand, melanin liberated from rubbing of the pigmented iris epithelium against lens structures results in reduced aqueous outflow with the risk of glaucoma, a condition called pigment dispersion syndrome.85
Pigmentation Pathways and Microphtalmia-Associated Transcription Factor as New Targets in Melanoma
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
These results suggest that MITF regulates both pigmentation and melanocyte proliferation and survival in a context-dependent manner. Although MITF is an amplified oncogene in only a minority of melanomas, its lineage survival role appears to extend to melanomas in which MITF is not amplified. For example, melanoma cell lines lacking MITF amplification still remain dependent on MITF for proliferation/survival. Whereas elevated MITF expression is generally associated with pigmentation/differentiation within melanocytes, it is unclear how MITF amplification in melanoma induces oncogenic transformation and overcomes the potential restraints associated with differentiation. Perhaps inactivation of the Rb or p53 pathway cooperates with MITFamplification in driving oncogenesis. Collectively, these observations indicate that in the context of many melanomas, targeting the MITF pathway may offer a therapeutic approach. Given that transcription factors are notoriously difficult to target by chemical biologic approaches, identification of critical upstream or downstream mediators of MITF function in melanomas is an area of intensive evaluation.
Clear cell sarcoma: state-of-the art and perspectives
Published in Expert Review of Anticancer Therapy, 2023
Laureline Wetterwald, Nicolò Riggi, Anastasios Kyriazoglou, Giovanni Dei Tos, Angelo Dei Tos, Antonia Digklia
The EWS::ATF1 oncoprotein behaves as an aberrant transcriptional activator, inducing an oncogenic expression program in CCS tumors. As an example, EWS::ATF1 directly binds and activates the promoter of MITF (Melanocyte Inducing Transcription Factor) in collaboration with the SRY-related HMG-box 10 (SOX10) transcription factor, resulting in tumor cell proliferation and melanocytic differentiation [30]. MITF also regulates the expression of several genes, one of the particular interest being the oncogenic receptor tyrosine kinase MET [31]. Indeed, it has been demonstrated that MET and its downstream pathways PI3K/AKT and ERK play a critical role in CCS oncogenesis [30,32]. Although CCSs share similar clinical, pathological, and genomic features with melanoma, BRAF pathway is not a main actor in its oncogenesis. Indeed, a recent series revealed that BRAF and NRAS are rarely mutated in CSS, with BRAF V599E and NRAS codon 61 mutations found in only 4.5% and 9% of cases, respectively [33]. Rarely, CCS tumors harboring BRAF pVal600Glu mutations have been reported.
A feasibility study of circulating melanoma cells in the perioperative context of hyperthermic isolated limb perfusion (HILP) in 20 patients
Published in International Journal of Hyperthermia, 2021
Dimosthenis Michelakis, Konstantinos Lasithiotakis, Ippokratis Messaritakis, Christos Ioannou, Kostas Perisynakis, Ioannis Souglakos, Dimitrios Stamatiou, Gregory Chlouverakis, Eelco de Bree, Ioannis Romanos, Odysseas Zoras
We note that the clone of CMCs, which was isolated during our measurements, expresses MITF in most patients. MITF is recognized as a key conductor of melanoma progression. It appears to act as a ‘rheostat,’ integrating various signals regulating its expression and activity to yield a variable output that translates into differential biological phenotypes [32]. Melanoma cells expressing MITF at a high level can either differentiate or proliferate. Low activity of MITF is related to stem cell-like or invasive potential. MITF expression and activity in melanoma cells are determined by genetic alterations, epigenetics, changes in upstream signaling pathways, and microenvironment [33]. The quantitative measure of expression is mostly heterogeneous, and immunological staining identifies ‘MITF -positive’ cells expressing higher and lower levels of MITF, but also cells that lack MITF expression entirely. Melanoma cells labeled as MITF positive populations can have low levels of MITF expression [34]. Finally, there may be cells with high expression of MITF mRNA, which does not lead to protein production, so in reality, there is a MITFlow melanoma [35].
Integrating transcriptome-wide association study and mRNA expression profiling identified candidate genes and pathways associated with osteomyelitis
Published in Scandinavian Journal of Rheumatology, 2020
L Zhang, Y Du, Y Wen, M Ma, S Cheng, B Cheng, P Li, X Qi, C Liang, L Liu, X Liang, X Guo, F Zhang
Another notable gene is CCDC50. CCDC50 encodes a tyrosine-phosphorylated protein with multiple ubiquitin-interacting domains. CCDC50 protein is a negative regulator of nuclear factor-κB (NF-κB) signalling. The receptor activator of nuclear factor NF-κB ligand (RANKL) has been shown to have important roles in the process of osteoclast realization (17). RANKL is a key osteoclastogenic cytokine. In the nucleus, activated NF-κB and T cells-2 (NFATc2) initiated the early activation of NFATc1, which subsequently combined with MITF, AP-1, PU.1, and cAMP response element-binding protein to induce the expression of osteoclast-specific genes (18). A previous study found that surface protein A induced osteoclast differentiation and promoted bone resorption in vitro, and the NF-κB ligand (RANKL) played an important role in this process (19).