Advances in biological regulation最新文献

Phosphatidic acid phosphatase, a conserved eukaryotic enzyme that catalyzes the Mg²⁺-dependent dephosphorylation of phosphatidic acid to produce diacylglycerol, has emerged as a vital regulator of lipid homeostasis. By controlling the balance of phosphatidic acid and diacylglycerol, the enzyme governs the use of the lipids for synthesis of the storage lipid triacylglycerol and the membrane phospholipids needed for cell growth. The mutational, biochemical, and cellular analyses of yeast phosphatidic acid phosphatase have provided insights into the structural determinants of enzyme function with the understanding of its regulation by phosphorylation and dephosphorylation. The key role that the enzyme plays in triacylglycerol synthesis indicates it may be a potential drug target to ameliorate obesity in humans. The enzyme activity, which is critical to the growth and virulence of pathogenic fungi, is a proposed target for therapeutic development to ameliorate fungal infections.

TP53 is normally a tumor suppressor. However, it is mutated in at least 50% of human cancers. Usually, we assume that mutation of the TP53 is associated with loss of sensitivity to various drugs as in most cases wild type (WT) TP53 activity is lost. This type of mutations is often dominant-negative (DN) mutations as they can interfere with the normal functions of WT-TP53 which acts as a tetramer. These mutations can result in altered gene expression patterns. There are some TP53 mutations which may lack some of the normal functions of TP53 but have additional functions; these types of mutations are called gain of function (GOF) mutations. There is another class of TP53 mutations, they are TP53 null mutations as the cells have deleted the TP53 gene (TP53-null). Although TP53 mutations were initially considered undruggable, other approaches have been developed to increase TP53 activity. One approach was to develop mouse double minute 2 homolog (MDM2) inhibitors as MDM2 suppresses TP53 activity. In addition, there have been mutant TP53 reactivators created, which will at least partially restore some of the critical growth suppressing effects of TP53. Some of these mutant TP53 reactivators have shown promise in clinical trial in certain types of cancer patients, especially myelodysplastic syndrome (MDS). In this review, we summarize the development of novel TP53 reactivators and MDM2 inhibitors. Both approaches are aimed at increasing or restoring TP53 activity. Attempts to increase TP53 activity in various TP53 mutant tumors could increase therapy of multiple deadly diseases.

Janus kinases (JAK1-3, TYK2) are critical mediators of cytokine signaling and their role in hematological and inflammatory and autoimmune diseases has sparked widespread interest in their therapeutic targeting. JAKs have unique tandem kinase structure consisting of an active tyrosine kinase domain adjacent to a pseudokinase domain that is a hotspot for pathogenic mutations. The development of JAK inhibitors has focused on the active kinase domain and the developed drugs have demonstrated good clinical efficacy but due to off-target inhibition cause also side-effects and carry a black box warning limiting their use. Our understanding of the regulatory function of the pseudokinase domain in physiological and pathological signaling has improved substantially. The pseudokinase domain maintains the inactive state of JAKs in the absence of cytokine stimulation but it has also a key role in physiological and mutation-driven activation process. Furthermore, the pseudokinase domain has favourable structural characteristics for selective targeting of cytokine signaling, such as unique mode of ATP-binding, and the first pseudokinase targeting inhibitor for TYK2 has been approved for clinical use. Here we describe the recent functional and structural knowledge of JAK signaling and their therapeutic targeting, and present data evaluating the druggability of the JAK3 pseudokinase domain.

Mitochondrial long chain fatty acid β-oxidation is a critical central carbon catabolic process. The importance of fatty acid oxidation is made evident by the life-threatening disease associated with diverse inborn errors in the pathway. While inborn errors show multisystemic requirements for fatty acid oxidation, it is not clear from the clinical presentation of these enzyme deficiencies what the tissue specific roles of the pathway are compared to secondary systemic effects. To understand the cell or tissue specific contributions of fatty acid oxidation to systemic physiology, conditional knockouts in mice have been employed to determine the requirements of fatty acid oxidation in disparate cell types. This has produced a host of surprising results that sometimes run counter to the canonical view of this metabolic pathway. The rigor of conditional knockouts has also provided clarity over previous research utilizing cell lines in vitro or small molecule inhibitors with dubious specificity. Here we will summarize current research using mouse models of Carnitine Palmitoyltransferases to determine the tissue specific roles and requirements of long chain mitochondrial fatty acid β-oxidation.

Key signaling pathways within the Bone Marrow Microenvironment (BMM), such as Notch, Phosphoinositide-Specific Phospholipase C (PI-PLCs), Transforming Growth Factor β (TGF-β), and Nuclear Factor Kappa B (NF-κB), play a vital role in the progression of Myelodysplastic Neoplasms (MDS). Among the various BMM cell types, Mesenchymal Stromal Cells (MSCs) are particularly central to these pathways. While these signaling routes can independently affect both MSCs and Hematopoietic Stem Cells (HSCs), they most importantly alter the dynamics of their interactions, leading to abnormal changes in survival, differentiation, and quiescence. Notch and PI-PLC signaling facilitate intercellular communication, TGF-β promotes quiescence and suppresses hematopoiesis, and NF-κB-driven inflammatory responses foster an environment detrimental to normal hematopoiesis. This review highlights the role of these pathways within the MDS microenvironment, driving the development and progression of the disease and paving the way for new possible therapeutic strategies.

The liquid-liquid phase separation in the cell nucleus regulates various processes such as gene regulation and transcription control, chromatin organization, and DNA repair. A plethora of proteins and RNAs contribute to the formation of biomolecular condensates and recently, several nuclear phosphoinositides were shown to be a part of these membrane-less complexes within the nucleus as well. Here we lipid-interacting RNA sequencing (LIPRNAseq) and confocal microscopy to uncover the RNA-binding capacity and localization of phosphatidylinositol 4,5 bisphosphate (PIP2). We discovered the consensus PIP2-binding AU-rich RNA motif and identified long non-coding RNA HANR (lncHANR) to colocalize with PIP2 in the proximity to the nucleolus in the perinucleolar compartment (PNC). Colocalization studies with different nuclear markers reveal that PIP2-HANR presence in the PNC correlates with oncogenic super-enhancers, and both PNC and oncogenic enhancers are part of the same structure. As lncHANR, PNC, and oncogenic super-enhancers are associated with cancer cell lines and tumors, we suggest that they can serve as interchangeable prognostic markers. Understanding of the interplay between lipid metabolism, and lncRNAs in subnuclear compartment phase separation can lead to future improvement in treatment strategies and personalized cancer management approaches.

The Trans Golgi Network (TGN)/endosomal system is a sorting center for cargo brought via the anterograde secretory pathway and the endocytic pathway that internalizes material from the plasma membrane. As many of the cargo that transit this central trafficking hub are components of key homeostatic signaling pathways, TGN/endosomes define a critical signaling hub for cellular growth control. A particularly interesting yet incompletely understood aspect of regulation of TGN/endosome function is control of this system by two families of lipid exchange/lipid transfer proteins. The phosphatidylinositol transfer proteins promote pro-trafficking phosphoinositide (i.e. phosphatidylinositol-4-phosphate) signaling pathways whereas proteins of the oxysterol binding protein family play reciprocal roles in antagonizing those arms of phosphoinositide signaling. The precise mechanisms for how these lipid binding proteins execute their functions remain to be resolved. Moreover, information regarding the coupling of individual members of the oxysterol binding protein family to specific biological activities is particularly sparse. Herein, we review what is being learned regarding functions of the oxysterol binding protein family in the yeast model system. Focus is primarily directed at a discussion of the Kes1/Osh4 protein for which the most information is available.

The phosphoinositide 3-kinase (PI3K) superfamily includes lipid kinases (PI3Ks and type III PI4Ks) and a group of PI3K-like Ser/Thr protein kinases (PIKKs: mTOR, ATM, ATR, DNA-PKcs, SMG1 and TRRAP) that have a conserved C-terminal kinase domain. A common feature of the superfamily is that they have very low basal activity that can be greatly increased by a range of regulatory factors. Activators reconfigure the active site, causing a subtle realignment of the N-lobe of the kinase domain relative to the C-lobe. This realignment brings the ATP-binding loop in the N-lobe closer to the catalytic residues in the C-lobe. In addition, a conserved C-lobe feature known as the PIKK regulatory domain (PRD) also can change conformation, and PI3K activators can alter an analogous PRD-like region. Recent structures have shown that diverse activating influences can trigger these conformational changes, and a helical region clamping onto the kinase domain transmits regulatory interactions to bring about the active site realignment for more efficient catalysis. A recent report of a small-molecule activator of PI3Kα for application in nerve regeneration suggests that flexibility of these regulatory elements might be exploited to develop specific activators of all PI3K superfamily members. These activators could have roles in wound healing, anti-stroke therapy and treating neurodegeneration. We review common structural features of the PI3K superfamily that may make them amenable to activation.