In the HAX1/HtrA2-OMI/PARL (HOP) mitochondrial protein complex, anti-apoptotic signals are generated by cleavage and activation of the serine protease HtrA2/OMI by the rhomboid protease PARL upon recruitment of both proteases to inner mitochondrial membrane protein HAX1 (HS1-associated protein X-1). Here we report the negative regulation of the HOP complex by human leukemia-associated myeloid leukemia factor 1 (MLF1). We demonstrate that MLF1 physically and functionally associates with HAX1 and HtrA2. Increased interaction of MLF1 with HAX1 and HtrA2 displaces HtrA2 from the HOP complex and inhibits HtrA2 cleavage and activation, resulting in the apoptotic cell death. Conversely, over-expressed HAX1 neutralizes MLF1's effect and inhibits MLF1-induced apoptosis. Importantly, Mlf1 deletion reverses B- and T-cell lymphopenia and significantly ameliorates the progressive striatal and cerebellar neurodegeneration observed in Hax1 mice, with a doubling of the lifespan of Mlf1/Hax1 animals compared to Hax1 animals. Collectively, these data indicate that MLF1 serves as a proapoptotic antagonist that interacts with the HOP mitochondrial complex to modulate cell survival.
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http://dx.doi.org/10.1016/j.bbamcr.2017.01.016 | DOI Listing |
Drug Dev Res
February 2025
Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, Egypt.
New phthalazine-derived inhibitors for VEGFR-2 were synthesized for anticancer evaluations. Also, docking studies were performed to explore the suggested binding orientations of the novel derivatives inside the binding site of VEGFR-2. The achieved biological data were extremely interrelated to that of docking study.
View Article and Find Full Text PDFBr J Pharmacol
December 2024
INSERM UMR1149/Inflammation Research Center (CRI), Team "From Inflammation to Cancer in Digestive diseases (INDiD)", DHU UNITY, Université Paris Cité, Paris, France.
Background And Purpose: Orexins have important biological effects on the central and peripheral nervous systems. Their primary ability is to regulate the sleep-wake cycle. Orexins and their antagonists, via OX receptor have been shown to have proapoptotic and antitumor effects on various digestive cancers cell models.
View Article and Find Full Text PDFDrug Des Devel Ther
December 2024
Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China.
Introduction: Acute kidney injury (AKI) is characterized by a significant reduction in kidney function and the accumulation of metabolites such as Creatinine (CRE) and Blood Urea Nitrogen (BUN). Levistolide A (LA), an active component of Ligusticum chuanxiong, offers multiple therapeutic benefits, including cardiovascular and neuroprotection, antitumor and analgesic effects, as well as anti-inflammatory, antioxidant, antifibrotic, and proapoptotic actions. However, the underlying mechanism of LA in treating AKI has not been fully elucidated.
View Article and Find Full Text PDFJ Transl Med
December 2024
Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, No. 1650 Taiwan Boulevard, Sect. 4, Taichung, 407219, Taiwan.
Background: Bortezomib is a standard treatment for multiple myeloma (MM), working by the accumulation of toxic misfolded proteins in cancer cells. However, a significant clinical challenge arises from the development of resistance to bortezomib in MM treatment. Aggresome, a subcellular structure enclosed within Vimentin, forms in response to proteasome inhibitors and sequesters misfolded proteins that are transported by histone deacetylase 6 (HDAC6) and Dynein for degradation via autophagy, thereby reducing bortezomib's cytotoxic effects.
View Article and Find Full Text PDFCells
November 2024
Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Overexpression of the anti-apoptotic protein BCL-2 is a key factor in the pathogenesis of chronic lymphocytic leukemia (CLL) and is associated with poor clinical outcomes. Therapeutic activation of apoptosis in cancer cells using the BCL-2 inhibitor (BCL2i) venetoclax has shown remarkable efficacy in clinical trials, both as monotherapy and combination regimens. However, patients with CLL experience a highly variable clinical course, facing significant challenges in advanced stages due to disease relapse and the emergence of resistant clones.
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