A Strong Loss-of-Function Mutation in RAN1 Results in Constitutive Activation of the Ethylene Response Pathway as Well as a Rosette-Lethal Phenotype

2000 ◽  
Vol 12 (3) ◽  
pp. 443 ◽  
Author(s):  
Keith E. Woeste ◽  
Joseph J. Kieber
Keyword(s):  
Loss Of Function ◽  
Constitutive Activation ◽  
Lethal Phenotype ◽  
Ethylene Response

scholarly journals Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease

PLoS ONE ◽  
2019 ◽  
Vol 14 (8) ◽  
pp. e0221482 ◽  
Author(s):  
Yuji Nakamura ◽  
Kohji Kato ◽  
Naomi Tsuchida ◽  
Naomichi Matsumoto ◽  
Yoshiyuki Takahashi ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Constitutive Activation ◽  
Neurodevelopmental Disease ◽  
Mtorc1 Signaling

scholarly journals Membrane protein MHZ3 stabilizes OsEIN2 in rice by interacting with its Nramp-like domain

2018 ◽  
Vol 115 (10) ◽  
pp. 2520-2525 ◽  
Author(s):  
Biao Ma ◽  
Yang Zhou ◽  
Hui Chen ◽  
Si-Jie He ◽  
Yi-Hua Huang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Ethylene Signaling ◽  
Loss Of Function ◽  
Wild Type ◽  
Protein Ubiquitination ◽  
Ethylene Response ◽  
Gene And Protein Expression ◽  
Domain Loss ◽  
Ethylene Insensitivity ◽  
Insight Into

The phytohormone ethylene regulates many aspects of plant growth and development. EIN2 is the central regulator of ethylene signaling, and its turnover is crucial for triggering ethylene responses. Here, we identified a stabilizer of OsEIN2 through analysis of the rice ethylene-response mutant mhz3. Loss-of-function mutations lead to ethylene insensitivity in etiolated rice seedlings. MHZ3 encodes a previously uncharacterized membrane protein localized to the endoplasmic reticulum. Ethylene induces MHZ3 gene and protein expression. Genetically, MHZ3 acts at the OsEIN2 level in the signaling pathway. MHZ3 physically interacts with OsEIN2, and both the N- and C-termini of MHZ3 specifically associate with the OsEIN2 Nramp-like domain. Loss of mhz3 function reduces OsEIN2 abundance and attenuates ethylene-induced OsEIN2 accumulation, whereas MHZ3 overexpression elevates the abundance of both wild-type and mutated OsEIN2 proteins, suggesting that MHZ3 is required for proper accumulation of OsEIN2 protein. The association of MHZ3 with the Nramp-like domain is crucial for OsEIN2 accumulation, demonstrating the significance of the OsEIN2 transmembrane domains in ethylene signaling. Moreover, MHZ3 negatively modulates OsEIN2 ubiquitination, protecting OsEIN2 from proteasome-mediated degradation. Together, these results suggest that ethylene-induced MHZ3 stabilizes OsEIN2 likely by binding to its Nramp-like domain and impeding protein ubiquitination to facilitate ethylene signal transduction. Our findings provide insight into the mechanisms of ethylene signaling.

scholarly journals Canonical Wnt signaling exerts bidirectional control on choroid plexus epithelial development

2020 ◽  
Author(s):  
Arpan Parichha ◽  
Varun Suresh ◽  
Mallika Chatterjee ◽  
Aditya Kshirsagar ◽  
Lihi Ben-Reuven ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Choroid Plexus ◽  
Embryonic Stem ◽  
Mammalian Brain ◽  
Loss Of Function ◽  
Canonical Wnt Signaling ◽  
Constitutive Activation ◽  
Cortical Hem ◽  
And Function ◽  
Canonical Wnt

AbstractThe choroid plexus (CP) secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the CP epithelium (CPe) arises from the Wnt- and Bmp- expressing cortical hem. We examined the role of canonical Wnt signaling in CPe development and report that the mouse and human embryonic CPe expresses molecules in this pathway. Either loss of function or constitutive activation of β-catenin, a key mediator of canonical Wnt signaling, causes a profound disruption of mouse CPe development. Loss of β-catenin results in a dysmorphic CPe, while constitutive activation of β-catenin causes a loss of CPe identity and a transformation of this tissue to a hippocampal-like identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell (hESC)-derived organoids. Our results indicate that canonical Wnt signaling is required in a precisely regulated manner for normal CP development in the mammalian brain.

scholarly journals Wnt/β-catenin signaling is required for the development of multiple nephron segments

2018 ◽  
Author(s):  
Patrick Deacon ◽  
Charles W Concodora ◽  
Eunah Chung ◽  
Joo-Seop Park
Keyword(s):  
Kidney Development ◽  
Critical Role ◽  
Proximal Tubules ◽  
Loss Of Function ◽  
Constitutive Activation ◽  
Nephron Segments ◽  
Mesenchymal To Epithelial Transition ◽  
Nephron Progenitors ◽  
Distal Tubules ◽  
Nephron Progenitor

The nephron is composed of distinct segments that perform unique physiological functions to generate urine. Little is known about how multipotent nephron progenitor cells differentiate into different nephron segments. It is well known that Wnt/β-catenin signaling regulates the maintenance and commitment of mesenchymal nephron progenitors during kidney development. However, it is not fully understood how it regulates nephron patterning after nephron progenitors undergo mesenchymal-to-epithelial transition. To address this, we performed β-catenin loss-of-function and gain-of-function studies in epithelial nephron progenitors in the mouse kidney. Consistent with a previous report, the formation of the renal corpuscle was defective in the absence of β-catenin. Interestingly, we found that epithelial nephron progenitors lacking β-catenin were able to form presumptive proximal tubules but that they failed to further develop into differentiated proximal tubules, suggesting that Wnt/β-catenin signaling plays a critical role in proximal tubule development. We also found that epithelial nephron progenitors lacking β-catenin failed to form the distal tubules. Constitutive activation of Wnt/β-catenin signaling blocked the proper formation of all nephron segments, suggesting tight regulation of Wnt/β-catenin signaling during nephron patterning. This work shows that Wnt/β-catenin signaling regulates the patterning of multiple nephron segments along the proximo-distal axis of the mammalian nephron.

scholarly journals Growth- and stress-related defects associated to wall hypoacetylation are strigolactone-dependent

2018 ◽  
Author(s):  
Vicente Ramírez ◽  
Guangyan Xiong ◽  
Kiyoshi Mashiguchi ◽  
Shinjiro Yamaguchi ◽  
Markus Pauly
Keyword(s):  
Direct Effect ◽  
Freezing Tolerance ◽  
Suppressor Mutation ◽  
Compensatory Mechanism ◽  
Biosynthetic Gene ◽  
Loss Of Function ◽  
Strong Reduction ◽  
Branch Number ◽  
Biochemical Evidence ◽  
Constitutive Activation

ABSTRACTMutants affected in the Arabidopsis TBL29/ESK1 xylan O-acetyltransferase display a strong reduction in total wall O-acetylation accompanied by a dwarfed plant stature, collapsed xylem morphology, and enhanced freezing tolerance. A newly identified tbl29/esk1 suppressor mutation affects the biosynthesis of strigolactones (SL) due to the reduced expression of the MAX4 gene. Genetic and biochemical evidence suggests that blocking the biosynthesis of SL is sufficient to recover all developmental and stress-related defects associated with the TBL29/ESK1 loss of function without affecting its direct effect - reduced wall O-acetylation. Altered levels of the MAX4 SL biosynthetic gene, reduced branch number, and higher levels of methyl carlactonoate, an active SL, were also found in tbl29/esk1 plants consistent with a constitutive activation of the SL pathway. These results indicate that the reduction of O-acetyl substituents in xylan is not directly responsible for the observed tbl29/esk1 phenotypes. Alternatively, plants may perceive defects in the structure of wall polymers and/or wall architecture activating the SL hormonal pathway as a compensatory mechanism.

scholarly journals Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response

2002 ◽  
Vol 196 (5) ◽  
pp. 589-604 ◽  
Author(s):  
Matthias Ernst ◽  
Melissa Inglese ◽  
Glen M. Scholz ◽  
Kenneth W. Harder ◽  
Fiona J. Clay ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Tyrosine Kinases ◽  
Physiological Role ◽  
Lung Parenchyma ◽  
Innate Immune ◽  
Lung Pathology ◽  
Loss Of Function ◽  
Constitutive Activation

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated HckF/F “knock-in” mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y499-residue in the Hck protein. Unlike their Hck−/− “loss-of-function” counterparts, HckF/F “gain-of-function” mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from HckF/F mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), HckF/F mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)α. Similarly, HckF/F mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from HckF/F mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFα production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in HckF/F mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage.

scholarly journals A loss-of-function mutation in the nucleoporin AtNUP160 indicates that normal auxin signalling is required for a proper ethylene response in Arabidopsis

2012 ◽  
Vol 63 (5) ◽  
pp. 2231-2241 ◽  
Author(s):  
L. M. Robles ◽  
S. D. Deslauriers ◽  
A. A. Alvarez ◽  
P. B. Larsen
Keyword(s):  
Loss Of Function ◽  
Ethylene Response ◽  
Auxin Signalling

scholarly journals cdc2 and the regulation of mitosis: six interacting mcs genes.

Genetics ◽  
1989 ◽  
Vol 122 (4) ◽  
pp. 773-782 ◽  
Author(s):  
L Molz ◽  
R Booher ◽  
P Young ◽  
D Beach
Keyword(s):  
Protein Kinase ◽  
Double Mutant ◽  
Mitotic Catastrophe ◽  
Temperature Sensitive ◽  
Loss Of Function ◽  
Wild Type ◽  
Diverse Range ◽  
Lethal Phenotype ◽  
Suppressor Mutations ◽  
A Cell

Abstract A cdc2-3w weel-50 double mutant of fission yeast displays a temperature-sensitive lethal phenotype that is associated with gross abnormalities of chromosome segregation and has been termed mitotic catastrophe. In order to identify new genetic elements that might interact with the cdc2 protein kinase in the regulation of mitosis, we have isolated revertants of the lethal double mutant. The suppressor mutations define six mcs genes (mcs: mitotic catastrophe suppressor) that are not allelic to any of the following mitotic control genes: cdc2, wee 1, cdc13, cdc25, suc1 or nim1. Each mcs mutation is recessive with respect to wild-type in its ability to suppress mitotic catastrophe. None confer a lethal phenotype as a single mutant but few of the mutants are expected to be nulls. A diverse range of genetic interactions between the mcs mutants and other mitotic regulators were uncovered, including the following examples. First, mcs2 cdc2w or mcs6 cdc2w double mutants display a cell cycle defect dependent on the specific wee allele of cdc2. Second, both mcs1 cdc25-22 or mcs4 cdc25-22 double mutants are nonconditionally lethal, even at a temperature normally permissive for cdc25-22. Finally, the characteristic suppression of the cdc25 phenotype by a loss-of-function wee1 mutation is reversed in a mcs3 mutant background. The mcs genes define new mitotic elements that might be activators or substrates of the cdc2 protein kinase.

E3 ubiquitin ligases

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson
Keyword(s):  
Protein Complexes ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Protein Ubiquitination ◽  
C Terminus ◽  
Full Complement ◽  
Spatio Temporal ◽  
Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

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