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"Xiao, Wei"
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TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target
High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.
Depletion of tribbles pseudokinase 3 (TRIB3) is known to suppress the expression of several tumor-promoting factors, including EGFR. Here, the authors show that TRIB3 interacts with EGFR and regulates its stability and activity, and perturbing EGFR-TRIB3 interaction attenuates NSCLC progression by accelerating EGFR degradation.
Journal Article
Apple B-box protein BBX37 regulates jasmonic acid mediated cold tolerance through the JAZ-BBX37-ICE1-CBF pathway and undergoes MIEL1-mediated ubiquitination and degradation
• The plant hormone jasmonic acid (JA) is involved in the cold stress response, and the inducer of CBF expression 1 (ICE1)- C-repeat binding factor (CBF) regulatory cascade plays a key role in the regulation of cold stress tolerance. In this study, we showed that a novel B-box (BBX) protein MdBBX37 positively regulates JA-mediated cold-stress resistance in apple.
• We found that MdBBX37 bound to the MdCBF1 and MdCBF4 promoters to activate their transcription, and also interacted with MdICE1 to enhance the transcriptional activity of MdICE1 on MdCBF1, thus promoting its cold tolerance.
• Two JA signaling repressors, MdJAZ1 and MdJAZ2 (JAZ, JAZMONATE ZIM-DOMAIN), interacted with MdBBX37 to repress the transcriptional activity of MdBBX37 on MdCBF1 and MdCBF4, and also interfered with the interaction between MdBBX37 and MdICE1, thus negatively regulating JA-mediated cold tolerance. E3 ligase MdMIEL1 (MIEL1, MYB30-Interacting E3 Ligase1) reduced MdBBX37-improved cold resistance by mediating ubiquitination and degradation of the MdBBX37 protein.
• The data reveal that MIEL1 and JAZ proteins co-regulate JA-mediated cold stress tolerance through the BBX37-ICE1-CBF module in apple. These results will aid further examination of the post-translational modification of BBX proteins and the regulatory mechanism of JA-mediated cold stress tolerance.
Journal Article
TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription
The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer.
Cancer stem cells contribute to breast cancer metastasis and recurrence. Here the authors show that TRIB3 enhances breast cancer stemness through interaction with AKT to promote FOXO1 stability, which then increases SOX2 activity.
Journal Article
Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy
Aberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of Aconitum carmichaelii , shows unique efficacy in reviving Yang for resuscitation, which has been widely used in clinics. As a main cardiotonic component of Fuzi, mesaconine has been proven effective in various cardiomyopathy models. Here, we aimed to define a previously unrevealed cardioprotective mechanism of mesaconine-mediated restoration of obstructive mitophagy. The functional implications of mesaconine were evaluated in doxorubicin (DOX)-induced heart failure models. DOX-treated mice showed characteristic cardiac dysfunction, ectopic myocardial energy disorder, and impaired mitophagy in cardiomyocytes, which could be remarkably reversed by mesaconine. The cardioprotective effect of mesaconine was primarily attributed to its ability to promote the restoration of mitophagy in cardiomyocytes, as evidenced by elevated expression of PINK1, a key mediator of mitophagy induction. Silencing PINK1 or deactivating mitophagy could completely abolish the protective effects of mesaconine. Together, our findings suggest that the cardioprotective effects of mesaconine appear to be dependent on the activation of PINK1-induced mitophagy and that mesaconine may constitute a promising therapeutic agent for the treatment of heart failure.
Journal Article
مبادئ الحكم في الصين القديمة
يتناول كتاب (مبادئ الحكم في الصين القديمة) والذي قامه بتأليفه (وي تشينغ) في حوالي (211) صفحة من القطع المتوسط موضوع (تاريخ الصين قديم) مستعرضا المحتويات التالية : قبل أكثر من ألف وربعمائة عام، أصدر الإمبراطور تاي تسونغ إمبراطور أسرة تانغ الملكية (618-907) مرسوما بأن يجمع أربعة من أشهر علماء الصين وسياسييها وأمهرهم وقتها المعارف التاريخية حول مبادئ الحكم الإمبراطوري من الكتب الكلاسيكية القديمة الستة، والمجموعات التاريخية الأربع، والمئات من مؤلفات المدارس الفكرية الصينية، وأن يرتبوها ويستخرجوا منها الدروس الاكثر اهمية حول تهذيب النفس وإصلاحها، وإدارة العائلة، والحكم الجيد للبلاد، وسبل جلب السلام للعالم. وكانت النتيجة مجموعة عنوانها \"تشيونشو تشيياو\" التي أقتبست بعناية من أربعة عشر ألف كتاب، وتسع وثمانين ألف مخطوطة من الكتابات القديمة، بإجمالي خمسمائة ألف فقرة مكتوبة، تغطي خمسة وشتين صنفا من الكتب. وقد ساعد هذا الكتاب الإمبراطور تاي سونغ والكثير من الأباطرة من بعده في أمور الحكم، ويعود الفضل في تحقيق الرخاء والسلام في المراحل اللاحقة بالصين القديمة بنسبة كبيرة إلى هذا الكتاب.
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MdWRKY40 promotes wounding-induced anthocyanin biosynthesis in association with MdMYB1 and undergoes MdBT2-mediated degradation
Wounding stress leads to anthocyanin accumulation. However, the underlying molecular mechanism remains elusive. In this study, MdWRKY40 was found to promote wounding-induced anthocyanin biosynthesis in association with MdMYB1 and undergo MdBT2-mediated degradation in apple.
We found that MdMYB1, a positive regulator of anthocyanin biosynthesis, was essential for the wounding-induced anthocyanin biosynthesis in apple. MdWRKY40 was identified as an MdMYB1-interacting protein, and enhanced the binding of MdMYB1 to its target genes in response to wounding.
We found that MdBT2 interacted physically with MdWRKY40 and was involved in its degradation through the 26S proteasome pathway.
Our results demonstrate that MdWRKY40 is a key modulator in the wounding-induced anthocyanin biosynthesis, which provides new insights into the regulation of wounding-induced anthocyanin biosynthesis at both the transcriptional and post-translational levels in apple.
Journal Article