UNC-45A is required for neurite extension via controlling NMII activation

UNC-45A is a highly conserved member of the UNC-45/CRO1/She4p family of proteins, which act as chaperones for conventional and nonconventional myosins. NMII mediates contractility and actin-based motility, which are fundamental for proper growth cone motility and neurite extension. The presence and role of UNC-45A in neuronal differentiation have been largely unknown. Here we demonstrate that UNC-45A is a novel growth cone–localized, NMII-associated component of the multiprotein complex regulating growth cone dynamics. We show that UNC-45A is dispensable for neuron survival but required for neurite elongation. Mechanistically, loss of UNC-45A results in increased levels of NMII activation. Collectively our results provide novel insights into the molecular mechanisms of neurite growth and define UNC-45A as a novel and master regulator of NMII-mediated cellular processes in neurons.

Download Full-text

Role of Long Non-Coding RNA Polymorphisms in Cancer Chemotherapeutic Response

Journal of Personalized Medicine ◽

10.3390/jpm11060513 ◽

2021 ◽

Vol 11 (6) ◽

pp. 513

Author(s):

Zheng Zhang ◽

Meng Gu ◽

Zhongze Gu ◽

Yan-Ru Lou

Keyword(s):

Molecular Mechanisms ◽

Neurological Diseases ◽

Cellular Processes ◽

Dna And Rna ◽

Chemotherapeutic Response ◽

Non Coding Rna ◽

Response To Chemotherapy ◽

Personalized Oncology ◽

Long Non Coding Rna

Genetic polymorphisms are defined as the presence of two or more different alleles in the same locus, with a frequency higher than 1% in the population. Since the discovery of long non-coding RNAs (lncRNAs), which refer to a non-coding RNA with a length of more than 200 nucleotides, their biological roles have been increasingly revealed in recent years. They regulate many cellular processes, from pluripotency to cancer. Interestingly, abnormal expression or dysfunction of lncRNAs is closely related to the occurrence of human diseases, including cancer and degenerative neurological diseases. Particularly, their polymorphisms have been found to be associated with altered drug response and/or drug toxicity in cancer treatment. However, molecular mechanisms are not yet fully elucidated, which are expected to be discovered by detailed studies of RNA–protein, RNA–DNA, and RNA–lipid interactions. In conclusion, lncRNAs polymorphisms may become biomarkers for predicting the response to chemotherapy in cancer patients. Here we review and discuss how gene polymorphisms of lncRNAs affect cancer chemotherapeutic response. This knowledge may pave the way to personalized oncology treatments.

Download Full-text

Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

Current Medicinal Chemistry ◽

10.2174/0929867324666170426095015 ◽

2018 ◽

Vol 25 (1) ◽

pp. 5-21 ◽

Cited By ~ 25

Author(s):

Ylenia Cau ◽

Daniela Valensin ◽

Mattia Mori ◽

Sara Draghi ◽

Maurizio Botta

Keyword(s):

Protein Interactions ◽

Molecular Mechanisms ◽

Physiological Role ◽

Specific Protein ◽

Protein Protein Interactions ◽

Cellular Processes ◽

Protein Partners ◽

High Sequence Homology ◽

Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

Download Full-text

Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease

Biochemical Journal ◽

10.1042/bj20110949 ◽

2011 ◽

Vol 439 (3) ◽

pp. 349-378 ◽

Cited By ~ 212

Author(s):

Anthony J. Morgan ◽

Frances M. Platt ◽

Emyr Lloyd-Evans ◽

Antony Galione

Keyword(s):

Molecular Mechanisms ◽

Cellular Processes ◽

Late Endosomes ◽

Wide Range ◽

Health And Disease ◽

Lysosome Related Organelles ◽

Cellular Compartments ◽

Endosomal Vesicles ◽

Intracellular Targets

Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.

Download Full-text

An exon DNA element modulates heterochromatin spreading in the master regulator for sexual commitment in malaria parasites

10.1101/2020.06.26.163105 ◽

2020 ◽

Author(s):

Carlos Cordon-Obras ◽

Anna Barcons-Simon ◽

Christine Scheidig-Benatar ◽

Aurelie Claës ◽

Valentin Sabatet ◽

...

Keyword(s):

Molecular Mechanisms ◽

Rna Binding ◽

Antigenic Variation ◽

Rna Binding Proteins ◽

Protein Complexes ◽

Heterochromatin Protein 1 ◽

Master Regulator ◽

Heterochromatin Protein

ABSTRACTHeterochromatin is essential in all eukaryotes to maintain genome integrity, long-term gene repression and to help chromosome segregation during mitosis. However, heterochromatin regions must be restricted by boundary elements to avoid its spreading over actively transcribed loci. In Plasmodium falciparum, facultative heterochromatin is important to regulate parasite virulence, antigenic variation and transmission. However, the underlying molecular mechanisms regulating repressive regions remain unknown. To investigate this topic, we chose the ap2-g gene, which forms a strictly delimited and independent heterochromatin island. Using electrophoretic motility shift assay (EMSA) we identified an ap2-g exon element at the 3’ end binding nuclear protein complexes. Upon replacement of this region by a gfp gene, we observed a shift in the heterochromatin boundary resulting in HP1 (Heterochromatin Protein 1) spreading over ∼2 additional kb downstream. We used this DNA element to purify candidate proteins followed by proteomic analysis. The identified complexes were found to be enriched in RNA-binding proteins, pointing to a potential role of RNA in the regulation of the ap2-g 3’ heterochromatin boundary. Our results provide insight into the unexplored topic of heterochromatin biology in P. falciparum and identify a DNA element within the master regulator of sexual commitment modulating heterochromatin spreading.

Download Full-text

When the chains do not break: the role of USP10 in physiology and pathology

Cell Death and Disease ◽

10.1038/s41419-020-03246-7 ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Udayan Bhattacharya ◽

Fiifi Neizer-Ashun ◽

Priyabrata Mukherjee ◽

Resham Bhattacharya

Keyword(s):

Complex Formation ◽

Molecular Mechanisms ◽

Protein Homeostasis ◽

Post Translational Modification ◽

Intracellular Protein ◽

Lysosomal Degradation ◽

Life Activity ◽

Cellular Processes ◽

Pathological Conditions

AbstractDeubiquitination is now understood to be as important as its partner ubiquitination for the maintenance of protein half-life, activity, and localization under both normal and pathological conditions. The enzymes that remove ubiquitin from target proteins are called deubiquitinases (DUBs) and they regulate a plethora of cellular processes. DUBs are essential enzymes that maintain intracellular protein homeostasis by recycling ubiquitin. Ubiquitination is a post-translational modification where ubiquitin molecules are added to proteins thus influencing activation, localization, and complex formation. Ubiquitin also acts as a tag for protein degradation, especially by proteasomal or lysosomal degradation systems. With ~100 members, DUBs are a large enzyme family; the ubiquitin-specific peptidases (USPs) being the largest group. USP10, an important member of this family, has enormous significance in diverse cellular processes and many human diseases. In this review, we discuss recent studies that define the roles of USP10 in maintaining cellular function, its involvement in human pathologies, and the molecular mechanisms underlying its association with cancer and neurodegenerative diseases. We also discuss efforts to modulate USPs as therapy in these diseases.

Download Full-text

Regulation of hemidesmosome dynamics and cell signaling by integrin α6β4

Journal of Cell Science ◽

10.1242/jcs.259004 ◽

2021 ◽

Vol 134 (18) ◽

Author(s):

Lisa te Molder ◽

Jose M. de Pereda ◽

Arnoud Sonnenberg

Keyword(s):

Signal Transduction ◽

Extracellular Matrix ◽

Cell Adhesion ◽

Epithelial Cells ◽

Basement Membrane ◽

Molecular Mechanisms ◽

Vital Role ◽

Cellular Processes ◽

Integrin Α6β4

ABSTRACT Hemidesmosomes (HDs) are specialized multiprotein complexes that connect the keratin cytoskeleton of epithelial cells to the extracellular matrix (ECM). In the skin, these complexes provide stable adhesion of basal keratinocytes to the underlying basement membrane. Integrin α6β4 is a receptor for laminins and plays a vital role in mediating cell adhesion by initiating the assembly of HDs. In addition, α6β4 has been implicated in signal transduction events that regulate diverse cellular processes, including proliferation and survival. In this Review, we detail the role of α6β4 in HD assembly and beyond, and we discuss the molecular mechanisms that regulate its function.

Download Full-text

HERC Ubiquitin Ligases in Cancer

Cancers ◽

10.3390/cancers12061653 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1653

Author(s):

Joan Sala-Gaston ◽

Arturo Martinez-Martinez ◽

Leonardo Pedrazza ◽

L. Francisco Lorenzo-Martín ◽

Rubén Caloto ◽

...

Keyword(s):

Immune Responses ◽

Tumor Suppressors ◽

Molecular Mechanisms ◽

Ubiquitin Ligases ◽

Tumor Type ◽

E3 Ligases ◽

Cellular Processes ◽

Damage Response ◽

Herc Proteins

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3–HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies.

Download Full-text

Role of the growth cone in neuronal differentiation

Molecular Neurobiology ◽

10.1007/bf02935590 ◽

1989 ◽

Vol 3 (1-2) ◽

pp. 101-133 ◽

Cited By ~ 11

Author(s):

C. O. M. Van Hooff ◽

A. B. Oestreicher ◽

P. N. E. De Graan ◽

W. H. Gispen

Keyword(s):

Neuronal Differentiation ◽

Growth Cone

Download Full-text

Rapid metabolic and bioenergetic adaptations of astrocytes under hyperammonemia – a novel perspective on hepatic encephalopathy

Biological Chemistry ◽

10.1515/hsz-2021-0172 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Marcel Zimmermann ◽

Andreas S. Reichert

Keyword(s):

Hepatic Encephalopathy ◽

Molecular Mechanisms ◽

Tca Cycle ◽

Therapeutic Strategies ◽

Cellular Processes ◽

Cellular Models ◽

The Tca Cycle ◽

Underlying Mechanisms

Abstract Hepatic encephalopathy (HE) is a well-studied, neurological syndrome caused by liver dysfunctions. Ammonia, the major toxin during HE pathogenesis, impairs many cellular processes within astrocytes. Yet, the molecular mechanisms causing HE are not fully understood. Here we will recapitulate possible underlying mechanisms with a clear focus on studies revealing a link between altered energy metabolism and HE in cellular models and in vivo. The role of the mitochondrial glutamate dehydrogenase and its role in metabolic rewiring of the TCA cycle will be discussed. We propose an updated model of ammonia-induced toxicity that may also be exploited for therapeutic strategies in the future.

Download Full-text

ZNF281 inhibits neuronal differentiation and is a prognostic marker for neuroblastoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801435115 ◽

2018 ◽

Vol 115 (28) ◽

pp. 7356-7361 ◽

Cited By ~ 17

Author(s):

Marco Pieraccioli ◽

Sara Nicolai ◽

Consuelo Pitolli ◽

Massimiliano Agostini ◽

Alexey Antonov ◽

...

Keyword(s):

Neuronal Differentiation ◽

Prognostic Marker ◽

Cortical Neurons ◽

Ectopic Expression ◽

Bioinformatic Analysis ◽

Cellular Processes ◽

Stage 4 ◽

Stage 1 ◽

Inappropriate Expression

Derangement of cellular differentiation because of mutation or inappropriate expression of specific genes is a common feature in tumors. Here, we show that the expression of ZNF281, a zinc finger factor involved in several cellular processes, decreases during terminal differentiation of murine cortical neurons and in retinoic acid-induced differentiation of neuroblastoma (NB) cells. The ectopic expression of ZNF281 inhibits the neuronal differentiation of murine cortical neurons and NB cells, whereas its silencing causes the opposite effect. Furthermore, TAp73 inhibits the expression of ZNF281 through miR34a. Conversely, MYCN promotes the expression of ZNF281 at least in part by inhibiting miR34a. These findings imply a functional network that includes p73, MYCN, and ZNF281 in NB cells, where ZNF281 acts by negatively affecting neuronal differentiation. Array analysis of NB cells silenced for ZNF281 expression identified GDNF and NRP2 as two transcriptional targets inhibited by ZNF281. Binding of ZNF281 to the promoters of these genes suggests a direct mechanism of repression. Bioinformatic analysis of NB datasets indicates that ZNF281 expression is higher in aggressive, undifferentiated stage 4 than in localized stage 1 tumors supporting a central role of ZNF281 in affecting the differentiation of NB. Furthermore, patients with NB with high expression of ZNF281 have a poor clinical outcome compared with low-expressors. These observations suggest that ZNF281 is a controller of neuronal differentiation that should be evaluated as a prognostic marker in NB.

Download Full-text