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Developmental Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James H. Tonsgard, Nikolas Mata-Machado
VHL is discussed in detail in Chapter 13. However, it is mentioned here because it is a neurocutaneous disorder and because its etiology and pathogenesis are related to stimulation of the mTOR signaling pathway, which is implicated in most of the other neurocutaneous disorders discussed in this chapter. The vHL gene is located on chromosome 3p and encodes a protein that acts as a tumor suppressor gene. The protein forms a complex with other proteins, including elongin B and C, and cullin 2, to form a VCB-CUL2 complex. The complex determines ubiquitin-dependent proteolysis of large cellular proteins. When normal oxygen levels are present, the complex binds to the α subunits of hypoxia-inducible factors (HIFs) 1 and 2 for degradation of proteins. If VHL protein is absent, HIF stimulates angiogenesis, which is critical in tumor formation.23
Phytochemistry of Harmal
Published in Ephraim Shmaya Lansky, Shifra Lansky, Helena Maaria Paavilainen, Harmal, 2017
Ephraim Shmaya Lansky, Shifra Lansky, Helena Maaria Paavilainen
Desoxypeganine derivatives were developed as inhibitors of NEDD8-activating enzyme (NAE), which regulates specific degradation of proteins controlled by cullin-RING ubiquitin E3 ligases. The inhibition was believed, based on molecular modeling, to be related to blocking of ATP binding domains, and the derivatives were considered lead molecules for the development of more effective NAE inhibitors (Zhong H.J. et al. 2012, 2015).
Multiple endocrine neoplasia type 2
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
In contrast to MTC, occult or de novo germline mutations in apparently sporadic PC presentations are relatively uncommon, and this is especially true if careful medical and family histories have been obtained. For example, the first series that systematically examined this issue comprised 48 apparently sporadic PC patients, among which only one (2%) was shown to have a germline RET mutation (Eng et al., 1995a). In this instance, when the referring clinician was asked to re-examine the patient, who was already a young adult, and first degree relatives, he discovered that the patient had an MTC, and the father had a large neck mass which was found to be MTC as well. Further, a more extensive family history revealed the index case’s paternal grandfather dying of ‘a goitre’ (Eng et al., 1995a). Three other series revealed no occult or de novo germline RET mutations in apparently isolated PC cases (Beldjord et al., 1995; Hofstra et al., 1996; Lindor et al., 1995). Recently, over-representation of polymorphic alleles of the CUL2 gene were described in sporadic PC cases originating from Brazil (Duerr et al., 1999). CUL2, a member of the cullin family believed to play a role in the ubiquitination-proteosome degradative pathway, binds the VHL/elongin-B/elongin-C complex (see Chapter 4). The precise mechanism of low penetrance susceptibility by CUL2 alleles is currently unknown.
Discovery of dual tubulin-NEDDylation inhibitors with antiproliferative activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
NEDDylation is catalysed by three-enzyme cascade including the E1 NEDD8-activating enzyme (NAE), E2 NEDD8-conjugating enzyme and E3 NEDD8 ligase, which could lead to attachment of ubiquitin-like NEDD8 to a substrate protein on a lysine residue8. Many studies have illustrated the close relationship between NEDDylation in multiple pathophysiological processes and different NEDDylation modulators were designed9. Compound 5 (Figure 2) as an orally bioavailable analogue inhibited both DCN1-mediated cullin neddylation and the DCN1-UBE2M protein-protein interaction10. Our group reported a novel tertiary amide derivative 6 as the NEDDylation activator to inhibit tumour progression in vitro and in vivo11. Compound 7 targeting NEDDylation displayed the potent activity MGC-803, EC-109, and PC-3 cells with IC50 values of 2.35, 10.1, and 5.71 μM12. All these findings showed that NEDDylation modulators might be potential anticancer agents.
The Markers Auxiliary in Differential Diagnosis of Early Melanomas and Benign Nevi Sharing Some Similar Features Potentially Leading to Misdiagnosis – A Review of Immunohistochemical Studies
Published in Cancer Investigation, 2022
Łukasz Kuźbicki, Anna A. Brożyna
The method for the improvement of the differential diagnosis of melanocytic skin lesions seems to be the simultaneous assessment of several markers. In a study conducted on 33 dysplastic nevi and 122 melanomas, 12 potential markers were immunohistochemically tested. Four molecules were selected for which the greatest differences between benign and malignant lesions were shown: BCL2-like protein 11 (Bim), Brahma-related gene-1 expression protein product (BRG1), cullin 1 (Cul1), and an inhibitor of growth family member 4 (ING4). When analyzing the efficiency of diagnostic tests based on the level of these proteins, the following AUC values were obtained: 0.72 for ING4-Cul1, 0.77 for ING4-Cul1-BRG1, and 0.84 for ING4-Cul1-BRG1-Bim (63). However, the group of examined melanomas included 74 primary melanomas without distant metastases and 48 metastatic melanomas, and the demonstrated AUC values were also available in other studies for single markers (Table 2). In another work, double staining of Ki-67 and Melan-A was performed for 233 common nevi, 2 Spitz nevi, 35 dysplastic nevi, 22 melanomas in situ, and 84 melanomas (including 48 cases with tumor thickness ≤1 mm). When the combined dermal and epidermal index for all examined lesions was analyzed, AUC = 0.89 was obtained. Importantly, for the diagnostic test of distinguishing melanomas in situ from junctional nevi based on the epidermal index, the AUC value amounted to only 0.66 (64).
Cyclin-dependent kinase inhibition and its intersection with immunotherapy in breast cancer: more than CDK4/6 inhibition
Published in Expert Opinion on Investigational Drugs, 2022
Xianan Guo, Huihui Chen, Yunxiang Zhou, Lu Shen, Shijie Wu, Yiding Chen
There are some findings illustrating the link between PD-L1 expression and response to ICIs [109,110], hence control of PD-L1 regulation could potentially convert non-responders to responders of anti-PD1/PD-L1 therapy. Notably, elevated PD-L1 levels were observed in CDK4/6i-treated preclinical models, and Zhang et al. delineated the potential rationale [6]. Cyclin D-CDK4-Cullin 3-speckle type POZ protein (SPOP) is involved in the expression of PD-L1. The inhibition of CDK4/6 compromises PD-L1 degradation by reducing cullin 3-SPOP ubiquitin ligase (Figure 2). Consistent with the downregulation of SPOP, CDK4/6i augments PD-L1 expression via suppression of RB hyper-phosphorylation (Figure 2) [111]. In addition, enhanced co-expression of PD-1 and CTLA-4 has been detected in CDK4/6i-treated tumors [112].