scholarly journals 14-3-3τ Regulates Ubiquitin-Independent Proteasomal Degradation of p21, a Novel Mechanism of p21 Downregulation in Breast Cancer

2010 ◽  
Vol 30 (6) ◽  
pp. 1508-1527 ◽  
Author(s):  
Bing Wang ◽  
Kang Liu ◽  
Hui-Yi Lin ◽  
Naresh Bellam ◽  
Shiyun Ling ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Matrix Protein ◽  
Proteasomal Degradation ◽  
Extracellular Matrix Protein ◽  
Cellular Functions ◽  
Mcf7 Cells ◽  
Potential Therapeutic Target ◽  
Tamoxifen Response ◽  
Primary Human Breast

ABSTRACT 14-3-3 proteins regulate many cellular functions, including proliferation. However, the detailed mechanisms by which they control the cell cycle remain to be fully elucidated. We report that one of the 14-3-3 isoforms, 14-3-3τ, is required for the G1/S transition through its role in ubiquitin-independent proteasomal degradation of p21. 14-3-3τ binds to p21, MDM2, and the C8 subunit of the 20S proteasome in G1 phase and facilitates proteasomal targeting of p21. This function of 14-3-3τ may be deregulated in cancer. The overexpression of 14-3-3τ is frequently found in primary human breast cancer and correlates with lower levels of p21 and shorter patient survival. Tenascin-C, an extracellular matrix protein involved in tumor initiation and progression and a known 14-3-3τ inducer, decreases p21 and abrogates adriamycin-induced G1/S arrest. It has been known that p21 is required for a proper tamoxifen response in breast cancer. We show that the overexpression of 14-3-3τ inhibits tamoxifen-induced p21 induction and growth arrest in MCF7 cells. Together, the findings of our studies strongly suggest a novel oncogenic role of 14-3-3τ by downregulating p21 in breast cancer. Therefore, 14-3-3τ may be a potential therapeutic target in breast cancer.

scholarly journals Carcinoma-associated fibroblasts derived exosomes modulate breast cancer cell stemness through exonic circHIF1A by miR-580-5p in hypoxic stress

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yanxia Zhan ◽  
Junxian Du ◽  
Zhihui Min ◽  
Li Ma ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Breast Cancer Cells ◽  
Hypoxic Stress ◽  
Cellular Functions ◽  
Breast Cancer Therapy ◽  
Array Analysis ◽  
Cancer Stroma ◽  
Carcinoma Associated Fibroblasts

AbstractHypoxia is a common phenomenon in solid tumors. The roles of exosomes from hypoxic breast cancer stroma are less studied. So, the study was aimed to investigate the role of exosomes from hypoxic cancer-associated fibroblasts (CAFs) cells in breast cancer. The circRNA array analysis was performed to screen differential expressed circRNAs between hypoxic and normoxic CAFs exosomes. Candidate circHIF1A (circ_0032138) was screened out and it was confirmed that circHIF1A was up-regulated in the exosomes from hypoxic CAFs and their exosomes. Through investigating cellular functions including cell proliferation and stem cell features, it was demonstrated that hypoxic CAFs exosomes transferred circHIF1A into breast cancer cells, which played an important role in cancer stem cell properties sponging miR-580-5p by regulating CD44 expression. In a summary, circHIF1A from hypoxic CAFs exosomes played an important role in stem cell properties of breast cancer. CircHIF1A may act as a target molecule of breast cancer therapy.

scholarly journals LTBP1 promotes fibrillin incorporation into the extracellular matrix

2021 ◽  
Author(s):  
Matthias Przyklenk ◽  
Veronika Georgieva ◽  
Fabian Metzen ◽  
Sebastian Mostert ◽  
Birgit Kobbe ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Wide Spectrum ◽  
Extracellular Matrix Protein ◽  
Connective Tissues ◽  
Pathogenic Variants ◽  
Human Pathology ◽  
Fibrillin 1

LTBP1 is a large extracellular matrix protein and an associated ligand of fibrillin-microfibrils. Knowledge of LTBP1 functions is largely limited to its role in targeting and sequestering TGFβ growth factors within the extracellular matrix, thereby regulating their bioavailability. However, the recent description of a wide spectrum of phenotypes in multiple tissues in patients harboring LTBP1 pathogenic variants suggests a multifaceted role of the protein in the homeostasis of connective tissues. To better understand the human pathology caused by LTBP1 deficiency it is important to investigate its functional role in extracellular matrix formation. In this study, we show that LTBP1 coordinates the incorporation of fibrillin-1 and -2 into the extracellular matrix in vitro. We also demonstrate that this function is differentially exerted by the two isoforms, the short and long forms of LTBP1. Thereby our findings uncover a novel TGFβ-independent LTBP1 function potentially contributing to the development of connective tissue disorders.

Abstract 474: ERK4-deficiency Potentiates the TAC-induced Increase in Collagen1-α 1 Messenger RNA in Mice

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Joelle Trepanier ◽  
Dharmendra D Dingar ◽  
Marc-Antoine Gillis ◽  
Pramod Sahadevan ◽  
Yan Fen Shi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Messenger Rna ◽  
Matrix Protein ◽  
Interstitial Fibrosis ◽  
Cardiac Fibroblasts ◽  
Primary Source ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Matrix Protein ◽  
Systolic And Diastolic Function

Cardiac hypertrophy, a common consequence of cardiopathologies such as hypertension and myocardial infarcts, involves formation of excessive interstitial fibrosis, which may impair cardiac function. Fibroblasts are the primary source of extracellular matrix protein. Extracellular-regulated kinase 4 (ERK4) is an atypical mitogen-activated protein kinase (MAPK). The regulation and role of ERK4 in the heart are currently unidentified and its only known target is MAP kinase-activated protein kinase 5 (MK5), a kinase involved in regulating fibroblast function. Following constriction of the transverse aorta (TAC), MK5 haplodeficient mice showed an attenuation of the TAC-induced increase in collagen 1-α 1 mRNA at 2-wk post-TAC and reduced hypertrophy 8-wk post-TAC. Further studies revealed MK5 immunoreactivity in cardiac fibroblasts but not myocytes. MK5 immunoprecipitates from whole heart contain ERK3 immunoreactivity, but not that of ERK4 or p38 MAPK. This study was to examine the role of ERK4 in myocardial structure, function, and remodeling 3-wk post-TAC. At 12 wk of age, echocardiographic imaging revealed systolic and diastolic function in male ERK4 -/- mice were similar to wild-type littermates (ERK4 +/+ ). Three weeks post-TAC, hypertrophy was similar in ERK4 +/+ and ERK4 -/- mice. Transcripts for BNP and βMHC increased to similar extent in TAC- ERK4 +/+ and TAC- ERK4 -/- mice. Two-way ANOVA indicated that ERK4 deficiency altered the effect of TAC on TGFβ 1 and collagen 1-α 1 transcript levels with each being higher in TAC-ERK4 -/- mice. Furthermore, MK5 immunoprecipitates from cardiac fibroblast lysates did not contain ERK4 immunoreactivity. Additional experiments revealed the presence of ERK4 immunoreactivity in myocytes but not fibroblasts. These results suggest 1) ERK4 may be involved in myocyte - fibroblast communication during myocardial remodeling and 2) in cardiac myocytes, ERK4 is part of a novel signaling cascade that does not involve MK5.

Role of mesenchymal nidogen for epithelial morphogenesis in vitro

Development ◽  
1994 ◽  
Vol 120 (7) ◽  
pp. 2003-2014 ◽  
Author(s):  
P. Ekblom ◽  
M. Ekblom ◽  
L. Fecker ◽  
G. Klein ◽  
H.Y. Zhang ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Northern Blotting ◽  
Epithelial Morphogenesis ◽  
Extracellular Matrix Protein ◽  
Epithelial Development ◽  
Morphogenesis In Vitro ◽  
Development In Vitro ◽  
Membrane Components

Recent biochemical studies suggested that the extracellular matrix protein nidogen is a binding molecule linking together basement membrane components. We studied its expression and role during development. By immunofluorescence and northern blotting, nidogen was found early during epithelial cell development of kidney and lung. Yet, in situ hybridization revealed that nidogen was not produced by epithelium but by the adjacent mesenchyme in both organs. Binding of mesenchymal nidogen to epithelial laminin may thus be a key event during epithelial development. This is supported by antibody perturbation experiments. Antibodies against the nidogen binding site on laminin B2 chain perturbed epithelial development in vitro in embryonic kidney and lung. Mesenchymal nidogen could be important for early stages of epithelial morphogenesis.

scholarly journals The clinical spectrum of the congenital myasthenic syndrome resulting from COL13A1 mutations

Brain ◽  
2019 ◽  
Vol 142 (6) ◽  
pp. 1547-1560 ◽  
Author(s):  
Pedro M. Rodríguez Cruz ◽  
Judith Cossins ◽  
Eduardo de Paula Estephan ◽  
Francina Munell ◽  
Kathryn Selby ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Matrix Protein ◽  
Neuromuscular Synapse ◽  
Extracellular Matrix Protein ◽  
Congenital Myasthenic Syndrome ◽  
Facial Dysmorphism ◽  
Feeding Difficulties ◽  
Myasthenic Syndrome ◽  
Over Time

Abstract Next generation sequencing techniques were recently used to show mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Animal studies showed COL13A1, a synaptic extracellular-matrix protein, is involved in the formation and maintenance of the neuromuscular synapse that appears independent of the Agrin-LRP4-MuSK-DOK7 acetylcholine receptor clustering pathway. Here, we report the phenotypic spectrum of 16 patients from 11 kinships harbouring homozygous or heteroallelic mutations in COL13A1. Clinical presentation was mostly at birth with hypotonia and breathing and feeding difficulties often requiring ventilation and artificial feeding. Respiratory crisis related to recurrent apnoeas, sometimes triggered by chest infections, were common early in life but resolved over time. The predominant pattern of muscle weakness included bilateral ptosis (non-fatigable in adulthood), myopathic facies and marked axial weakness, especially of neck flexion, while limb muscles were less involved. Other features included facial dysmorphism, skeletal abnormalities and mild learning difficulties. All patients tested had results consistent with abnormal neuromuscular transmission. Muscle biopsies were within normal limits or showed non-specific changes. Muscle MRI and serum creatine kinase levels were normal. In keeping with COL13A1 mutations affecting both synaptic structure and presynaptic function, treatment with 3,4-diaminopyridine and salbutamol resulted in motor and respiratory function improvement. In non-treated cases, disease severity and muscle strength improved gradually over time and several adults recovered normal muscle strength in the limbs. In summary, patients with COL13A1 mutations present mostly with severe early-onset myasthenic syndrome with feeding and breathing difficulties. Axial weakness is greater than limb weakness. Disease course improves gradually over time, which could be consistent with the less prominent role of COL13A1 once the neuromuscular junction is mature. This report emphasizes the role of collagens at the human muscle endplate and should facilitate the recognition of this disorder, which can benefit from pharmacological treatment.

scholarly journals Baicalein inhibits fibronectin-induced epithelial–mesenchymal transition by decreasing activation and upregulation of calpain-2

2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Yan Chen ◽  
Lin Chen ◽  
Duanyang Hong ◽  
Zongyue Chen ◽  
Jingyu Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Extracellular Matrix ◽  
Cellular Response ◽  
Matrix Protein ◽  
Epithelial Mesenchymal Transition ◽  
T Antigen ◽  
Extracellular Matrix Protein ◽  
Mesenchymal Transition ◽  
Calpain 2 ◽  
E Cadherin

AbstractThe extracellular matrix protein fibronectin (FN) facilitates tumorigenesis and the development of breast cancer. Inhibition of the FN-induced cellular response is a potential strategy for breast cancer treatment. In the present study, we investigated the effects of the flavonoid baicalein on FN-induced epithelial–mesenchymal transition (EMT) in MCF-10A breast epithelial cells and in a transgenic mouse MMTV-polyoma middle T antigen breast cancer model (MMTV-PyMT). Baicalein inhibited FN-induced migration, invasion, and F-actin remodeling. Baicalein also suppressed FN-induced downregulation of the epithelial markers E-cadherin and ZO-1 and upregulation of the mesenchymal markers N-cadherin, vimentin, and Snail. Further investigation revealed that calpain-2 was involved in baicalein suppression of FN-induced EMT. Baicalein significantly decreased FN-enhanced calpain-2 expression and activation by suppressing its plasma membrane localization, substrate cleavage, and degradation of its endogenous inhibitor calpastatin. Overexpression of calpain-2 in MCF-10A cells by gene transfection partially blocked the inhibitory effect of baicalein on FN-induced EMT changes. In addition, baicalein inhibited calpain-2 by decreasing FN-increased intracellular calcium ion levels and extracellular signal-regulated protein kinases activation. Baicalein significantly decreased tumor onset, growth, and pulmonary metastasis in a spontaneous breast cancer MMTV-PyMT mouse model. Baicalein also reduced the expression of FN, calpain-2, and vimentin, but increased E-cadherin expression in MMTV-PyMT mouse tumors. Overall, these results revealed that baicalein markedly inhibited FN-induced EMT by inhibiting calpain-2, thus providing novel insights into the pharmacological action and mechanism of baicalein. Baicalein may therefore possess therapeutic potential for the treatment of breast cancer though interfering with extracellular matrix–cancer cell interactions.

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