The lipid side of unfolded protein response.

Although our current knowledge of the molecular crosstalk between the ER stress, the unfolded protein response (UPR), and lipid homeostasis remains limited, there is increasing evidence that dysregulation of either protein or lipid homeostasis profoundly affects the other. Most research regarding UPR signaling in human diseases has focused on the causes and consequences of disrupted protein folding. The UPR itself consists of very complex pathways that function to not only maintain protein homeostasis, but just as importantly, modulate lipid biogenesis to allow the ER to adjust and promote cell survival.

EFR3A: a new raft domain organizing protein?

Background: Membrane rafts play a crucial role in the regulation of many important biological processes. Our previous data suggest that specific interactions of flotillins with MPP1 are responsible for membrane raft domain organization and regulation in erythroid cells. Interaction of the flotillin-based protein network with specific membrane components underlies the mechanism of raft domain formation and regulation, including in cells with low expression of MPP1.

Effect of LDHA Inhibition on TNF-α-Induced Cell Migration in Esophageal Cancers.

Cell migration is an essential part of the complex and multistep process that is the development of cancer, a disease that is the second most common cause of death in humans. An important factor promoting the migration of cancer cells is TNF-α, a pro-inflammatory cytokine that, among its many biological functions, also plays a major role in mediating the expression of MMP9, one of the key regulators of cancer cell migration. It is also known that TNF-α is able to induce the Warburg effect in some cells by increasing glucose uptake and enhancing the expression and activity of lactate dehydrogenase subunit A (LDHA).

In Vivo Models for Prostate Cancer Research.

In 2022, prostate cancer (PCa) is estimated to be the most commonly diagnosed cancer in men in the United States-almost 270,000 American men are estimated to be diagnosed with PCa in 2022. This review compares and contrasts in vivo models of PCa with regards to the altered genes, signaling pathways, and stages of tumor progression associated with each model. The main type of model included in this review are genetically engineered mouse models, which include conditional and constitutive knockout model.

MMP9: A Tough Target for Targeted Therapy for Cancer.

Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs.

The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma.

Inhibition of the protein neddylation process by the small-molecule inhibitor MLN4924 has been recently indicated as a promising direction for cancer treatment. However, the knowledge of all biological consequences of MLN4924 for cancer cells is still incomplete. Here, we report that MLN4924 inhibits tumor necrosis factor-alpha (TNF-α)-induced matrix metalloproteinase 9 (MMP9)-driven cell migration.

Invadopodia: clearing the way for cancer cell invasion.

The invasive nature of many cancer cells involves the formation of F-actin-based, lipid-raft-enriched membrane protrusions known as invadopodia or, more broadly, invadosomes. Invadopodia are specialized adhesive structures arising from ventral cell surface within cell-extracellular matrix (ECM) contacts and concentrate high proteolytic activities that allow cells to overcome the dense scaffold of local microenvironment, comprising a natural barrier to cell spreading. This degradative activity distinguishes invadopodia from other adhesive structures like focal adhesions, lamellipodia or filopodia, and is believed to drive cancer progression.

The role of cholesterol and cholesterol-driven membrane raft domains in prostate cancer.

Unlabelled: Membrane rafts are heterogeneous and dynamic domains that are characterized by tight packing of lipids. They are enriched in cholesterol, sphingolipids, and certain types of proteins. Among these are various cell signaling proteins, which indicate that rafts play an important role in cell signal transduction pathways, including some involved in cancer development, progression, and invasiveness.

Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling.

Background: Prostate cancer development involves various mechanisms, which are poorly understood but pointing to epithelial mesenchymal transition (EMT) as the key mechanism in progression to metastatic disease. ABI1, a member of WAVE complex and actin cytoskeleton regulator and adaptor protein, acts as tumor suppressor in prostate cancer but the role of ABI1 in EMT is not clear.

Methods: To investigate the molecular mechanism by which loss of ABI1 contributes to tumor progression, we disrupted the ABI1 gene in the benign prostate epithelial RWPE-1 cell line and determined its phenotype.

MPP1-based mechanism of resting state raft organization in the plasma membrane. Is it a general or specialized mechanism in erythroid cells?

Biological membranes are organized in various microdomains, one of the best known being called membrane rafts. The major function of these is thought to organize signaling partners into functional complexes. An important protein found in membrane raft microdomains of erythroid and other blood cells is MPP1 (membrane palmitoylated protein 1)/p55.

Bone marrow-specific loss of induces myeloproliferative neoplasm with features resembling human myelofibrosis.

Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showing that bone marrow-specific deletion of in a novel mouse model leads to development of an MPN-like phenotype resembling human PMF.

A novel regulatory function of CDKN1A/p21 in TNFα-induced matrix metalloproteinase 9-dependent migration and invasion of triple-negative breast cancer cells.

Metastasis is the leading cause of mortality in patients with highly invasive cancers and, as such, is a major problem for medicine. It has been increasingly recognized that cancer-related inflammation plays an important role in promoting invasion and the metastatic process in which cell motility and upregulation of proteolytic enzymes are crucial events. TNFα is a proinflammatory cytokine known to stimulate synthesis of MMP9, a zinc- and calcium-dependent endopeptidase contributing to the regulation of ECM remodeling and cell signaling.

Novel Concept and Method of Endoscopic Urethral Stricture Treatment Using Liquid Buccal Mucosal Graft.

Purpose: We describe a novel method of urethral stricture treatment using liquid buccal mucosal grafts to augment direct vision internal urethrotomy.

Materials And Methods: A rabbit stricture model was used to test this method. In phase 1 the concept of endoscopic liquid buccal mucosal graft implantation was tested by performing direct vision internal urethrotomy in 3 rabbits with immediate intraurethral injection of autologous liquid buccal mucosal grafts suspended in fibrin glue.

TNF-α promotes breast cancer cell migration and enhances the concentration of membrane-associated proteases in lipid rafts.

Purpose: Tumor progression is associated with cell migration, invasion and metastasis. These processes are accompanied by the activation of specific proteases that are either linked to cellular membranes or are secreted into extracellular spaces. TNF-α is known to play an important role in various aspects of tumor progression.

Lactate dehydrogenase 5: an old friend and a new hope in the war on cancer.

A hallmark of most cancer cells is an altered metabolism involving a shift to aerobic glycolysis with lactate production coupled with a higher uptake of glucose as the main source of energy. Lactate dehydrogenase 5 (LDH-5) catalyzes the reduction of pyruvate by NADH to form lactate, thus determining the availability of NAD(+) to maintain the continuity of glycolysis. It is therefore an important control point in the system of cellular energy release.

Upregulated expression and activation of membrane‑associated proteases in esophageal squamous cell carcinoma.

To better understand the role of membrane-associated proteolytic systems in the development of esophageal cancer, we studied the expression of two serine proteases, fibroblast activation protein-α (FAP-α) and dipeptidyl peptidase IV (DPPIV) and three metalloproteinases, matrix metalloproteinase (MMP)-2, MMP-9 and MT1-MMP in 24 primary esophageal squamous cell carcinoma (ESCC) tissues and paired non-cancer tissues. Using reverse-transcription PCR, western blotting and zymography, we showed that both serine proteases and all three metalloproteinases were highly altered in ESCC. A positive correlation between the expression of FAP-α and DPPIV and the activity of both gelatinases was found.

Spectrin and phospholipids - the current picture of their fascinating interplay.

The spectrin-based membrane skeleton is crucial for the mechanical stability and resilience of erythrocytes. It mainly contributes to membrane integrity, protein organization and trafficking. Two transmembrane protein macro-complexes that are linked together by spectrin tetramers play a crucial role in attaching the membrane skeleton to the cell membrane, but they are not exclusive.

Membrane rafts as a novel target in cancer therapy.

Membrane rafts are distinct plasma membrane microdomains that are enriched in sphingolipids and cholesterol. They organize receptors and their downstream molecules and regulate a number of intracellular signaling pathways. This review presents information on the dependence of several growth factor receptor signaling pathways on membrane rafts.

Spectrins: a structural platform for stabilization and activation of membrane channels, receptors and transporters.

This review focuses on structure and functions of spectrin as a major component of the membrane skeleton. Recent advances on spectrin function as an interface for signal transduction mediation and a number of data concerning interaction of spectrin with membrane channels, adhesion molecules, receptors and transporters draw a picture of multifaceted protein. Here, we attempted to show the current depiction of multitask role of spectrin in cell physiology.

The role of MPP1/p55 and its palmitoylation in resting state raft organization in HEL cells.

Here we show the crucial role of MPP1 in lateral membrane ordering/organization in HEL cells (derived from erythroid precursors). Biochemical analyses showed that inhibition of MPP1 palmitoylation or silencing of the MPP1 gene led to a dramatic decrease in the DRM fraction. This was accompanied by a reduction of membrane order as shown by fluorescence-lifetime imaging microscopy (FLIM) analyses.

The effect of the lipid-binding site of the ankyrin-binding domain of erythroid beta-spectrin on the properties of natural membranes and skeletal structures.

It was previously shown that the beta-spectrin ankyrin-binding domain binds lipid domains rich in PE in an ankyrin-dependent manner, and that its N-terminal sequence is crucial in interactions with phospholipids. In this study, the effect of the full-length ankyrin-binding domain of beta-spectrin on natural erythrocyte and HeLa cell membranes was tested. It was found that, when encapsulated in resealed erythrocyte ghosts, the protein representing the full-length ankyrin-binding domain strongly affected the shape and barrier properties of the erythrocyte membrane, and induced partial spectrin release from the membrane, while truncated mutants had no effect.

[The interactions of actin cell and membrane skeleton proteins with lipids].

The results of many studies indicate that many cytoskeletal proteins interact with lipids, or are regulated by phosphoinositides. Proteins may associate with membranes through specific domains, amphipathic helices and undefined motifs that interact through electrostatic or hydrophobic interactions. The interaction between specific proteins and certain lipids affect stabilization of lipid microdomains, which may provide an anchor for cytoskeletal proteins.

Monocyte protein signatures of disease severity in sickle cell anemia.

Using two-dimensional difference gel electrophoresis (2D DIGE) we have analyzed monocytes derived from 10 sickle cell disease patients (5 males and 5 females ages 12-18) to generate hypotheses regarding signature proteins that appear most positively and negatively correlated with vasoocclusive event rate. Signature proteins have been identified by tandem mass spectrometry. Based on the limited number of samples analyzed, the most negatively correlated proteins related to crises rate were transketolase and coronin in the membrane fraction and heat shock 70 kDa protein cognate 4, and adenylate kinase isoenzyme 2, mitochondrial found in the cytosolic fraction.

Lipid-binding role of betaII-spectrin ankyrin-binding domain.

It is known that erythroid and non-erythroid spectrins binding of vesicles and monolayers containing PE proved sensitive to inhibition by red blood cell ankyrin. We now show that the bacterially-expressed recombinant peptides representing betaII(brain)-spectrin's ankyrin-binding domain and its truncated mutants showed lipid-binding activity, although only those containing a full-length amino terminal fragment showed high to moderate affinity towards phospholipid mono- and bilayers and a substantial sensitivity of this binding to inhibition by ankyrin. These results are in accordance with our published data on betaI-spectrin's ankyrin-binding domain [Hryniewicz-Jankowska A, et al.