scholarly journals Dominant-Negative Effects of a Novel Mutated Ins2 Allele Causes Early-Onset Diabetes and Severe  -Cell Loss in Munich Ins2C95S Mutant Mice

Diabetes ◽  
2007 ◽  
Vol 56 (5) ◽  
pp. 1268-1276 ◽  
Author(s):  
N. Herbach ◽  
B. Rathkolb ◽  
E. Kemter ◽  
L. Pichl ◽  
M. Klaften ◽  
...  
Keyword(s):  
Early Onset ◽  
Cell Loss ◽  
Dominant Negative ◽  
Mutant Mice ◽  
Negative Effects ◽  
Onset Diabetes

scholarly journals DNAJC3 deficiency induces β-cell mitochondrial apoptosis and causes syndromic young-onset diabetes

2021 ◽  
Vol 184 (3) ◽  
pp. 459-472
Author(s):  
Maria Lytrivi ◽  
Valérie Senée ◽  
Paraskevi Salpea ◽  
Federica Fantuzzi ◽  
Anne Philippi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Early Onset ◽  
Cell Loss ◽  
Endoplasmic Reticulum Stress Response ◽  
Mitochondrial Apoptosis ◽  
Loss Of Function ◽  
Β Cells ◽  
Β Cell ◽  
Onset Diabetes

Objective DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK). Dnajc3 deficiency in mice causes pancreatic β-cell loss and diabetes. Loss-of-function mutations in DNAJC3 cause early-onset diabetes and multisystemic neurodegeneration. The aim of our study was to investigate the genetic cause of early-onset syndromic diabetes in two unrelated patients, and elucidate the mechanisms of β-cell failure in this syndrome. Methods Whole exome sequencing was performed and identified variants were confirmed by Sanger sequencing. DNAJC3 was silenced by RNAi in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells. β-cell function and apoptosis were assessed, and potential mediators of apoptosis examined. Results The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities. They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3. DNAJC3 silencing did not impair insulin content or secretion. Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA. Conclusions This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response. DNAJC3 deficiency may lead to β-cell loss through BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

scholarly journals Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?

Contact ◽  
2021 ◽  
Vol 4 ◽  
pp. 251525642110225
Author(s):  
Nica Borgese ◽  
Francesca Navone ◽  
Nobuyuki Nukina ◽  
Tomoyuki Yamanaka
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Dominant Negative ◽  
Negative Effects ◽  
Membrane Contact Sites ◽  
Familial Form ◽  
Main Driver ◽  
Mechanistic Basis ◽  
Lateral Sclerosis

Nearly twenty years ago a mutation in the VAPB gene, resulting in a proline to serine substitution (p.P56S), was identified as the cause of a rare, slowly progressing, familial form of the motor neuron degenerative disease Amyotrophic Lateral Sclerosis (ALS). Since then, progress in unravelling the mechanistic basis of this mutation has proceeded in parallel with research on the VAP proteins and on their role in establishing membrane contact sites between the ER and other organelles. Analysis of the literature on cellular and animal models reviewed here supports the conclusion that P56S-VAPB, which is aggregation-prone, non-functional and unstable, is expressed at levels that are insufficient to support toxic gain-of-function or dominant negative effects within motor neurons. Instead, insufficient levels of the product of the single wild-type allele appear to be required for pathological effects, and may be the main driver of the disease. In light of the multiple interactions of the VAP proteins, we address the consequences of specific VAPB depletion and highlight various affected processes that could contribute to motor neuron degeneration. In the future, distinction of specific roles of each of the two VAP paralogues should help to further elucidate the basis of p.P56S familial ALS, as well as of other more common forms of the disease.

scholarly journals Dominant Negative Mutants Implicate STAT5 in Myeloid Cell Proliferation and Neutrophil Differentiation

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4154-4166 ◽  
Author(s):  
Robert L. Ilaria ◽  
Robert G. Hawley ◽  
Richard A. Van Etten
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Cytokine Signaling ◽  
Transactivation Domain ◽  
Negative Effects ◽  
Murine Bone Marrow ◽  
Negative Effect

Abstract STAT5 is a member of the signal transducers and activation of transcription (STAT) family of latent transcription factors activated in a variety of cytokine signaling pathways. We introduced alanine substitution mutations in highly conserved regions of murine STAT5A and studied the mutants for dimerization, DNA binding, transactivation, and dominant negative effects on erythropoietin-induced STAT5-dependent transcriptional activation. The mutations included two near the amino-terminus (W255KR→AAA and R290QQ→AAA), two in the DNA-binding domain (E437E→AA and V466VV→AAA), and a carboxy-terminal truncation of STAT5A (STAT5A/▵53C) analogous to a naturally occurring isoform of rat STAT5B. All of the STAT mutant proteins were tyrosine phosphorylated by JAK2 and heterodimerized with STAT5B except for the WKR mutant, suggesting an important role for this region in STAT5 for stabilizing dimerization. The WKR, EE, and VVV mutants had no detectable DNA-binding activity, and the WKR and VVV mutants, but not EE, were defective in transcriptional induction. The VVV mutant had a moderate dominant negative effect on erythropoietin-induced STAT5 transcriptional activation, which was likely due to the formation of heterodimers that are defective in DNA binding. Interestingly, the WKR mutant had a potent dominant negative effect, comparable to the transactivation domain deletion mutant, ▵53C. Stable expression of either the WKR or ▵53C STAT5 mutants in the murine myeloid cytokine-dependent cell line 32D inhibited both interleukin-3–dependent proliferation and granulocyte colony-stimulating factor (G-CSF)–dependent differentiation, without induction of apoptosis. Expression of these mutants in primary murine bone marrow inhibited G-CSF–dependent granulocyte colony formation in vitro. These results demonstrate that mutations in distinct regions of STAT5 exert dominant negative effects on cytokine signaling, likely through different mechanisms, and suggest a role for STAT5 in proliferation and differentiation of myeloid cells.

scholarly journals Dominant-negative effects in prion diseases: insights from molecular dynamics simulations on mouse prion protein chimeras

2013 ◽  
Vol 31 (8) ◽  
pp. 829-840 ◽  
Author(s):  
Xiaojing Cong ◽  
Salvatore Bongarzone ◽  
Gabriele Giachin ◽  
Giulia Rossetti ◽  
Paolo Carloni ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Prion Protein ◽  
Prion Diseases ◽  
Dominant Negative ◽  
Negative Effects ◽  
Dynamics Simulations

A Novel Locus, Mody4, Distal to D7Mit189 on Chromosome 7 Determines Early-Onset NIDDM in Nonobese C57BL/6 (Akita) Mutant Mice

Diabetes ◽  
1997 ◽  
Vol 46 (5) ◽  
pp. 887-894 ◽  
Author(s):  
M. Yoshioka ◽  
T. Kayo ◽  
T. Ikeda ◽  
A. Koizuni
Keyword(s):  
Early Onset ◽  
Mutant Mice ◽  
Chromosome 7

scholarly journals High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes

Diabetologia ◽  
1999 ◽  
Vol 42 (9) ◽  
pp. 1131-1137 ◽  
Author(s):  
M. Lehto ◽  
C. Wipemo ◽  
S.-A. Ivarsson ◽  
C. Lindgren ◽  
M. Lipsanen-Nyman ◽  
...  
Keyword(s):  
High Frequency ◽  
Early Onset ◽  
Mitochondrial Genes ◽  
Onset Diabetes

The conserved ninth C-terminal heptad in thyroid hormone and retinoic acid receptors mediates diverse responses by affecting heterodimer but not homodimer formation

1993 ◽  
Vol 13 (9) ◽  
pp. 5725-5737
Author(s):  
M Au-Fliegner ◽  
E Helmer ◽  
J Casanova ◽  
B M Raaka ◽  
H H Samuels
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Dominant Negative ◽  
Heptad Repeat ◽  
Specific Response ◽  
Wild Type ◽  
Negative Effects ◽  
Related Factors ◽  
Response Element ◽  
Response Elements

The receptors for thyroid hormone (T3R), all-trans-retinoic acid (RAR), and 9-cis-retinoic acid (RXR) bind DNA response elements as homo- and heterodimers. The ligand-binding domains of these receptors contain nine conserved heptads proposed to play a role in dimerization. Mutant receptors with changes in the first or last hydrophobic amino acids in the highly conserved ninth heptad of chick T3R alpha [cT3R alpha(L365R) and cT3R(L372R)] and human RAR alpha (hRAR alpha) [hRAR(M377R) and hRAR(L384R)] reveal that this heptad is essential for certain heterodimeric interactions and for diverse functional activities. Without ligands, wild-type receptors form both homodimers and heterodimers, while these mutants form only homodimers. Surprisingly, the cognate ligand for each mutant enables heterodimer formation between cT3R(L365R) and RAR or RXR and between hRAR(M377R) and T3R or RXR. Both cT3R(L365R) and hRAR(M377R) mediate ligand-dependent transcriptional regulation. However, unlike the wild-type receptor, non-ligand-associated cT3R(L365R) does not suppress the basal activity of certain promoters containing thyroid hormone response elements, suggesting that this silencing effect of T3R is mediated by unliganded heterodimers of T3R and endogenous RXR or related factors. Heterodimerization is also necessary for the strong ligand-independent inhibition between T3R and RAR on a common response element, since the ninth-heptad mutants function as poor inhibitors. However, with a T3R-specific response element, hRAR(M377R) acts as a retinoic acid-dependent inhibitor of cT3R, indicating the importance of heterodimerization for this inhibition. Our studies also suggest that the ninth heptad is necessary for the dominant inhibition of wild-type T3Rs by mutant T3Rs, as has been found for the thyroid hormone-resistant syndrome in humans. Thus, the ninth heptad repeat is required for heterodimerization, suppression of basal promoter activity, and dominant negative effects of T3R and RAR. Lastly, the finding that cT3R(L365R) and hRAR(M377R) require ligands for heterodimer formation also raises the possibility that heterodimeric interactions are mediated by the ninth heptad without ligands but by a second region of these receptors with ligands.

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