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Dilated Cardiomyopathy
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Marco Merlo, Alessia Paldino, Giulia De Angelis, Gianfranco Sinagra
The genetic background of LVRR has been recently explored. Mutations in genes encoding cytoskeleton Z-disk (DES, FLNC, and DMD), obscurin-like 1 (OBSL1), nexilin F-actin binding protein (NEXN), myopalladin (MYPN), nebulette (NEBL), and LIM domain binding 3 (LDB3) have been associated with a lower rate of LVRR compared with TTN genotype in a study population of 152 DCM patients.79
Ganglioglioma
Published in Dongyou Liu, Tumors and Cancers, 2017
Mandana Behbahani, Hasan R. Syed, Tadanori Tomita, Christopher Kalhorn
Most recently, the PI3K-mTOR pathway, which is responsible for cell size, growth control, cortical development, and neuronal migration, has been shown to play a critical role in the specific pathogenesis of gangliogioma [7,8]. Mutational analysis of downstream tumor suppressor complexes involving TSC1 (hamartin) and TSC2 (tuberin) reveals gene alteration in TSC2, including polymorphism in intron 4 and exon 41 to be overrepresented in ganglioglioma. Concurrently, somatic mutation in intron 32 is identified in the glial portion but not within the neurons of ganglioglioma. An increased polymorphism within tuberin has been noted in ganglioglioma relative to that of normal brain tissue. In contrast, ezrin–radixin–moesin (ERB) proteins interacting with TSC1 to regulate cell adhesion and migration display high levels of aberrancy within dysplastic elements of glioneuronal lesions, such as ganglioglioma. Additionally, LIM domain-binding 2, a gene known to play a role in brain development, is reduced in expression, possibly highlighting the development of an aberrant neuronal network as a major etiology in ganglioglioma, as previously hypothesized [9]. Interestingly, recent genetic studies suggest against the involvement of known pathogenic genes, such as TP53, EGFR, and PTN, as contributors to gangliogioma [8].
Multiple endocrine neoplasia type 2
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Shc adaptor proteins have been shown to bind RET in vivo, which leads to activation of the RAS -MAP kinase (MAPK) pathway (Figure 3) (Asai et al., 1995; Santoro et al., 1995). The tyrosine residue Y1062 has been shown to play a significant role in She binding, among other adaptor molecules, as it is a multi-functional docking site (Asai et al., 1996). Y1062 appears to be a phosphorylation-dependent docking site for Shc and a phosphorylation-independent site for interaction with the membrane-anchored enigma through its LIM domain, the latter believed to play a role of positioning RET in the cellular membrane (Durick et al., 1996, 1998a). RET activation of the RAS-MAPK pathway is mediated by Shc and Grb2 or Grb2 alone.
LDB1-mediated transcriptional complexes are sensitive to islet stress
Published in Islets, 2022
Yanping Liu, Jessica D. Kepple, Anath Shalev, Chad S. Hunter
Our lab and others have shown that the LIM-homeodomain transcription factor, Islet-1 (ISL1), and interacting co-regulator, LIM domain-binding protein 1 (LDB1), are required for β-cell development and function.17–20 Comparative tissue- and cell-type-specific knockout mouse models revealed that LDB1:ISL1-containing complexes are necessary for β-cell development, identity, survival, and insulin secretory function via direct regulation of several key β-cell gene targets, including MafA, Pdx1, Slc2a2, Glp1r, among others.17–20 Previously published work from our lab utilizing in vitro protein interaction screens revealed the Single-Stranded DNA-Binding protein 3 (SSBP3, also called SSDP121,22) co-regulator participates in β-cell LDB1:ISL1 complexes and contributes to the regulation of MafA expression in β-cells.23 Further, ISL1 and LDB1 are maintained in human islets,19,20 highlighting the conservation and importance of these factors to mammalian β-cells and glucose homeostasis. However, little is known of whether the expression and/or interactions of ISL1 and LDB1 are modulated by β-cell stimuli or stressors.
Understanding intrinsic survival and regenerative pathways through in vivo and in vitro studies: implications for optic nerve regeneration
Published in Expert Review of Ophthalmology, 2021
The well-examined intracellular pathway of axonal guidance cues and their receptors on the RGCs is the Rho/Rho-associated protein kinase (ROCK)/LIM domain kinase (LIMK) pathway [62]. Koch et al. suggest that ROCK2 knockdown increased the survival of RGCs and attenuated axonal degeneration after optic nerve crush in adult rats [63]. Nogo is an axon growth inhibitor, and the lateral olfactory tract usher substance (LOTUS) is an inhibitor of Nogo receptor type 1. Kawakami et al. demonstrated that the soluble form of LOTUS promoted axonal regeneration in the optic nerve injury mice [64]. But they used 3-week-old mice, and thus, it may be difficult to translate the findings to optic nerve regeneration in adults. The results of a recent study indicated that semaphorin 3A negatively regulates RGC regeneration by ROCK2 after optic nerve crush [65]. Taken together, inhibition of ROCK may be one of therapeutic targets of optic nerve regeneration.
Inhibition of ELF3 confers synthetic lethality of PARP inhibitor in non-small cell lung cancer
Published in Journal of Receptors and Signal Transduction, 2021
Yan Wang, Min Zuo, Hongtao Jin, Meina Lai, Jinfeng Luo, Zhiqiang Cheng
EMT could regulate transcription factor, zinc finger E-box binding homeobox 1, to mediate DNA damage response [25,26]. Moreover, EMT could modulate DNA damage response pathways to regulate PARP inhibitor resistance [27]. The role of ELF3 on DNA damage response was then determined. Immunofluorescence analysis showed that inhibition of ELF3 increased γH2AX foci accumulation while decreased RAD51 foci in PARP inhibitor-resistant NSCLC cells. Double-strand breaks generally triggers phosphorylation of H2AX to produce γH2AX [28], and γH2AX recruits other proteins to generate assembly of DNA repair proteins, thus playing an important role in DNA damage response [29]. RAD51 participates in DNA damage repair [30], and functions as biomarker of HR-mediated DNA damage repair [31]. LIM-domain only 2 could increase of γH2AX and decrease of RAD51 to inhibit HR-mediated DNA damage repair, sensitize tumor cells to PARP inhibitor [32]. Inhibition of bromodomain containing 4 induced HR deficiency via increase of γH2AX and decrease of RAD51, thus confering synthetic lethal with PARP inhibitors [33]. Therefore, inhibition of ELF3 reduced HR-mediated DNA damage repair ability in PARP inhibitor-resistant NSCLC cells. However, in addition to HR-mediated DNA damage repair, alternative NHEJ also participates in synthetic lethal therapies for PARP inhibitors [34]. The regulatory ability of ELF3 on NHEJ-mediated DNA damage repair in PARP inhibitor-resistant NSCLC cells should be further investigated.