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1.
PLoS One ; 19(3): e0297356, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38466708

RESUMO

Mitosis is the process by which eukaryotic cells divide to produce two similar daughter cells with identical genetic material. Research into the process of mitosis is therefore of critical importance both for the basic understanding of cell biology and for the clinical approach to manifold pathologies resulting from its malfunctioning, including cancer. In this paper, we propose an approach to study mitotic progression automatically using deep learning. We used neural networks to predict different mitosis stages. We extracted video sequences of cells undergoing division and trained a Recurrent Neural Network (RNN) to extract image features. The use of RNN enabled better extraction of features. The RNN-based approach gave better performance compared to classifier based feature extraction methods which do not use time information. Evaluation of precision, recall, and F-score indicates the superiority of the proposed model compared to the baseline. To study the loss in performance due to confusion between adjacent classes, we plotted the confusion matrix as well. In addition, we visualized the feature space to understand why RNNs are better at classifying the mitosis stages than other classifier models, which indicated the formation of strong clusters for the different classes, clearly confirming the advantage of the proposed RNN-based approach.


Assuntos
Mitose , Redes Neurais de Computação
2.
J Cell Sci ; 137(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38465513

RESUMO

Drosophila neural stem cells, or neuroblasts, rapidly proliferate during embryonic and larval development to populate the central nervous system. Neuroblasts divide asymmetrically to create cellular diversity, with each division producing one sibling cell that retains the neuroblast fate and another that differentiates into glia or neurons. This asymmetric outcome is mediated by the transient polarization of numerous factors to the cell cortex during mitosis. The powerful genetics and outstanding imaging tractability of the neuroblast make it an excellent model system for studying the mechanisms of cell polarity. This Cell Science at a Glance article and the accompanying poster explore the phases of the neuroblast polarity cycle and the regulatory circuits that control them. We discuss the key features of the cycle - the targeted recruitment of proteins to specific regions of the plasma membrane and multiple phases of highly dynamic actomyosin-dependent cortical flows that pattern both protein distribution and membrane structure.


Assuntos
Proteínas de Drosophila , Células-Tronco Neurais , Animais , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Mitose , Proteínas de Ciclo Celular/metabolismo , Polaridade Celular/fisiologia
3.
J Cell Biol ; 223(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38477879

RESUMO

A cell dealing with a broken chromosome in mitosis is like a driver dealing with a flat tire on the highway: damage repair must occur under non-ideal circumstances. Mitotic chromosome breaks encounter problems related to structures called micronuclei. These aberrant nuclei are linked to cell death, mutagenesis, and cancer. In the last few years, a flurry of studies illuminated two mechanisms that prevent mitotic problems related to micronuclei. One mechanism prevents micronuclei from forming during mitosis and involves DNA Polymerase Theta, a DNA repair regulator that patches up broken mitotic chromosomes. A second mechanism is activated after micronuclei form and then rupture, and involves CIP2A and TOPBP1 proteins, which patch micronuclear fragments to promote their subsequent mitotic segregation. Here, we review recent progress in this field of mitotic DNA damage and discuss why multiple mechanisms exist. Future studies in this exciting area will reveal new DNA break responses and inform therapeutic strategies.


Assuntos
Núcleo Celular , Quebra Cromossômica , Reparo do DNA , Mitose , Humanos , Morte Celular , Cromossomos , Animais
4.
Life Sci Alliance ; 7(5)2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38479814

RESUMO

Entry into mitosis requires not only correct DNA replication but also extensive cell reorganization, including the separation of the Golgi ribbon into isolated stacks. To understand the significance of pre-mitotic Golgi reorganization, we devised a strategy to first block Golgi segregation, with the consequent G2-arrest, and then force entry into mitosis. We found that the cells forced to enter mitosis with an intact Golgi ribbon showed remarkable cell division defects, including spindle multipolarity and binucleation. The spindle defects were caused by reduced levels at the centrosome of the kinase Aurora-A, a pivotal spindle formation regulator controlled by Golgi segregation. Overexpression of Aurora-A rescued spindle formation, indicating a crucial role of the Golgi-dependent recruitment of Aurora-A at the centrosome. Thus, our results reveal that alterations of the pre-mitotic Golgi segregation in G2 have profound consequences on the fidelity of later mitotic processes and represent potential risk factors for cell transformation and cancer development.


Assuntos
Citocinese , Mitose , Complexo de Golgi , Centrossomo
5.
J Cell Biol ; 223(5)2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448162

RESUMO

The septin cytoskeleton is extensively regulated by posttranslational modifications, such as phosphorylation, to achieve the diversity of architectures including rings, hourglasses, and gauzes. While many of the phosphorylation events of septins have been extensively studied in the budding yeast Saccharomyces cerevisiae, the regulation of the kinases involved remains poorly understood. Here, we show that two septin-associated kinases, the LKB1/PAR-4-related kinase Elm1 and the Nim1/PAR-1-related kinase Gin4, regulate each other at two discrete points of the cell cycle. During bud emergence, Gin4 targets Elm1 to the bud neck via direct binding and phosphorylation to control septin hourglass assembly and stability. During mitosis, Elm1 maintains Gin4 localization via direct binding and phosphorylation to enable timely remodeling of the septin hourglass into a double ring. This mutual control between Gin4 and Elm1 ensures that septin architecture is assembled and remodeled in a temporally controlled manner to perform distinct functions during the cell cycle.


Assuntos
Citoesqueleto , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Septinas , Ciclo Celular , Mitose , Fosforilação , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Septinas/genética
6.
Nat Commun ; 15(1): 2089, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38453961

RESUMO

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.


Assuntos
Hipertermia Induzida , Neoplasias Ovarianas , Feminino , Humanos , Proteína Quinase CDC2/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Tirosina Quinases/metabolismo , Multiômica , Mitose , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/patologia
7.
Cell Death Dis ; 15(3): 222, 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38493150

RESUMO

Unlike normal cells, cancer cells frequently exhibit supernumerary centrosomes, leading to formation of multipolar spindles that can trigger cell death. Nevertheless, cancer cells with supernumerary centrosomes escape the deadly consequences of unequal segregation of genomic material by coalescing their centrosomes into two poles. This unique trait of cancer cells presents a promising target for cancer therapy, focusing on selectively attacking cells with supernumerary centrosomes. Nek2A is a kinase involved in mitotic regulation, including the centrosome cycle, where it phosphorylates linker proteins to separate centrosomes. In this study, we investigated if Nek2A also prevents clustering of supernumerary centrosomes, akin to its separation function. Reduction of Nek2A activity, achieved through knockout, silencing, or inhibition, promotes centrosome clustering, whereas its overexpression results in inhibition of clustering. Significantly, prevention of centrosome clustering induces cell death, but only in cancer cells with supernumerary centrosomes, both in vitro and in vivo. Notably, none of the known centrosomal (e.g., CNAP1, Rootletin, Gas2L1) or non-centrosomal (e.g., TRF1, HEC1) Nek2A targets were implicated in this machinery. Additionally, Nek2A operated via a pathway distinct from other proteins involved in centrosome clustering mechanisms, like HSET and NuMA. Through TurboID proximity labeling analysis, we identified novel proteins associated with the centrosome or microtubules, expanding the known interaction partners of Nek2A. KIF2C, in particular, emerged as a novel interactor, confirmed through coimmunoprecipitation and localization analysis. The silencing of KIF2C diminished the impact of Nek2A on centrosome clustering and rescued cell viability. Additionally, elevated Nek2A levels were indicative of better patient outcomes, specifically in those predicted to have excess centrosomes. Therefore, while Nek2A is a proposed target, its use must be specifically adapted to the broader cellular context, especially considering centrosome amplification. Discovering partners such as KIF2C offers fresh insights into cancer biology and new possibilities for targeted treatment.


Assuntos
Centrossomo , Neoplasias , Humanos , Ciclo Celular , Morte Celular , Centrossomo/metabolismo , Análise por Conglomerados , Cinesinas/genética , Cinesinas/metabolismo , Microtúbulos/metabolismo , Mitose , Neoplasias/genética , Neoplasias/metabolismo , Fuso Acromático/metabolismo
8.
Sci Adv ; 10(10): eadn2706, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457507

RESUMO

The evolution of multicellularity paved the way for the origin of complex life on Earth, but little is known about the mechanistic basis of early multicellular evolution. Here, we examine the molecular basis of multicellular adaptation in the multicellularity long-term evolution experiment (MuLTEE). We demonstrate that cellular elongation, a key adaptation underpinning increased biophysical toughness and organismal size, is convergently driven by down-regulation of the chaperone Hsp90. Mechanistically, Hsp90-mediated morphogenesis operates by destabilizing the cyclin-dependent kinase Cdc28, resulting in delayed mitosis and prolonged polarized growth. Reinstatement of Hsp90 or Cdc28 expression resulted in shortened cells that formed smaller groups with reduced multicellular fitness. Together, our results show how ancient protein folding systems can be tuned to drive rapid evolution at a new level of biological individuality by revealing novel developmental phenotypes.


Assuntos
Evolução Biológica , Proteínas de Choque Térmico HSP90 , Proteínas de Choque Térmico HSP90/metabolismo , Mitose , Dobramento de Proteína , Fenótipo
9.
Cell Mol Life Sci ; 81(1): 141, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38485766

RESUMO

Human papillomavirus (HPV) infection is a primary cause of cervical and head-and-neck cancers. The HPV genome enters the nucleus during mitosis when the nuclear envelope disassembles. Given that lamins maintain nuclear integrity during interphase, we asked to what extent their loss would affect early HPV infection. To address this question, we infected human cervical cancer cells and keratinocytes lacking the major lamins with a HPV16 pseudovirus (HP-PsV) encoding an EGFP reporter. We found that a sustained reduction or complete loss of lamin B1 significantly increased HP-PsV infection rate. A corresponding greater nuclear HP-PsV load in LMNB1 knockout cells was directly related to their prolonged mitotic window and extensive nuclear rupture propensity. Despite the increased HP-PsV presence, EGFP transcript levels remained virtually unchanged, indicating an additional defect in protein turnover. Further investigation revealed that LMNB1 knockout led to a substantial decrease in autophagic capacity, possibly linked to the persistent activation of cGAS by cytoplasmic chromatin exposure. Thus, the attrition of lamin B1 increases nuclear perviousness and attenuates autophagic capacity, creating an environment conducive to unrestrained accumulation of HPV capsids. Our identification of lower lamin B1 levels and nuclear BAF foci in the basal epithelial layer of several human cervix samples suggests that this pathway may contribute to an increased individual susceptibility to HPV infection.


Assuntos
Lamina Tipo B , Infecções por Papillomavirus , Feminino , Humanos , Lamina Tipo B/genética , Lamina Tipo B/metabolismo , Infecções por Papillomavirus/genética , Membrana Nuclear/metabolismo , Mitose , Cromossomos/metabolismo , Lamina Tipo A/genética , Lamina Tipo A/metabolismo
10.
Mol Biol Cell ; 35(4): pe1, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38517328

RESUMO

Chromosomes and karyotypes are particularly rich in oddities and extremes. Described below are 10 remarkable chromosomes and karyotypes sprinkled throughout the tree of life. These include variants in chromosome number, structure, and dynamics both natural and engineered. This versatility highlights the robustness and tolerance of the mitotic and meiotic machinery to dramatic changes in chromosome and karyotype architecture. These examples also illustrate that the robustness comes at a cost, enabling the evolution of chromosomes that subvert mitosis and meiosis.


Assuntos
Cromossomos , Meiose , Cromossomos/genética , Cariótipo , Cariotipagem , Meiose/genética , Mitose
11.
Biochem Biophys Res Commun ; 706: 149741, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38471204

RESUMO

The chromosome passenger complex (CPC) is a kinase complex formed by Aurora B, borealin, survivin and inner centromere protein (INCENP). The CPC is active during mitosis and contributes to proper chromosome segregation via the phosphorylation of various substrates. Overexpression of each CPC component has been reported in most cancers. However, its significance remains unclear, as only survivin is known to confer chemoresistance. This study showed that the overexpression of borealin, a CPC component, stabilized survivin protein depending on its interaction with survivin. Unexpectedly, the accumulation of survivin by borealin overexpression did not affect the well-characterized functions of survivin, such as chemoresistance and cell proliferation. Interestingly, the overexpression of borealin promoted lactate production but not the overexpression of the deletion mutant that lacks the ability to bind to survivin. Consistent with these findings, the expression levels of glycolysis-related genes were enhanced in borealin-overexpressing cancer cells. Meanwhile, the overexpression of survivin alone did not promote lactate production. Overall, the accumulation of the borealin-survivin complex promoted glycolysis in squamous cell carcinoma cells. This mechanism may contribute to cancer progression via excessive lactate production.


Assuntos
Carcinoma de Células Escamosas , Centrômero , Humanos , Survivina/genética , Survivina/metabolismo , Centrômero/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ciclo Celular/metabolismo , Mitose , Fosforilação , Aurora Quinase B/genética , Aurora Quinase B/metabolismo , Carcinoma de Células Escamosas/genética , Lactatos
12.
PLoS One ; 19(3): e0296779, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38478555

RESUMO

The mitotic spindle is the bipolar, microtubule-based structure that segregates chromosomes at each cell division. Aberrant spindles are frequently observed in cancer cells, but how oncogenic transformation affects spindle mechanics and function, particularly in the mechanical context of solid tumors, remains poorly understood. Here, we constitutively overexpress the oncogene cyclin D1 in human MCF10A cells to probe its effects on spindle architecture and response to compressive force. We find that cyclin D1 overexpression increases the incidence of spindles with extra poles, centrioles, and chromosomes. However, it also protects spindle poles from fracturing under compressive force, a deleterious outcome linked to multipolar cell divisions. Our findings suggest that cyclin D1 overexpression may adapt cells to increased compressive stress, possibly contributing to its prevalence in cancers such as breast cancer by allowing continued proliferation in mechanically challenging environments.


Assuntos
Centrossomo , Ciclina D1 , Humanos , Centríolos , Ciclina D1/genética , Mitose , Oncogenes , Fuso Acromático/genética
13.
Nat Commun ; 15(1): 2441, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38499565

RESUMO

Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.


Assuntos
Lipídeos , Mitose , Animais , Ciclo Celular , Fase G1 , Fosforilação , Mamíferos
14.
Open Biol ; 14(3): 230440, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38442865

RESUMO

Microtubule organization and reorganization during the cell cycle are achieved by regulation of the number, distribution and activity of microtubule-organizing centres (MTOCs). In fission yeast, the Mto1/2 complex determines the activity and distribution of cytoplasmic MTOCs. Upon mitosis, cytoplasmic microtubule nucleation ceases; inactivation of the Mto1/2 complex is triggered by Mto2 hyperphosphorylation. However, the protein kinase(s) that phosphorylates Mto2 remains elusive. Here we show that a conserved signalling network, called MOR (morphogenesis Orb6 network) in fission yeast, negatively regulates cytoplasmic MTOCs through Mto2 phosphorylation to ensure proper microtubule organization. Inactivation of Orb6 kinase, the most downstream MOR component, by attenuation of MOR signalling leads to reduced Mto2 phosphorylation, coincident with increased number of both Mto2 puncta and cytoplasmic microtubules. These defects cause the emergence of uncoordinated mitotic cells with cytoplasmic microtubules, resulting in reduced spindle assembly. Thus, the regulation of Mto2 by the MOR is crucial for cytoplasmic microtubule organization and contributes to reorganization of the microtubule cytoskeletons during the cell cycle.


Assuntos
Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Ciclo Celular , Mitose , Fosforilação , Microtúbulos , Proteínas Serina-Treonina Quinases , Proteínas de Ciclo Celular , Proteínas de Schizosaccharomyces pombe/genética
15.
Biochem Soc Trans ; 52(1): 29-39, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38305688

RESUMO

Accurate chromosome segregation in mitosis relies on sister kinetochores forming stable attachments to microtubules (MTs) extending from opposite spindle poles and establishing biorientation. To achieve this, erroneous kinetochore-MT interactions must be resolved through a process called error correction, which dissolves improper kinetochore-MT attachment and allows new interactions until biorientation is achieved. The Aurora B kinase plays key roles in driving error correction by phosphorylating Dam1 and Ndc80 complexes, while Mps1 kinase, Stu2 MT polymerase and phosphatases also regulate this process. Once biorientation is formed, tension is applied to kinetochore-MT interaction, stabilizing it. In this review article, we discuss the mechanisms of kinetochore-MT interaction, error correction and biorientation. We focus mainly on recent insights from budding yeast, where the attachment of a single MT to a single kinetochore during biorientation simplifies the analysis of error correction mechanisms.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomycetales , Saccharomyces cerevisiae/genética , Cinetocoros , Microtúbulos/genética , Mitose , Segregação de Cromossomos , Proteínas de Saccharomyces cerevisiae/genética
16.
Biochem Soc Trans ; 52(1): 455-464, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38372373

RESUMO

Transcription represents a central aspect of gene expression with RNA polymerase machineries (RNA Pol) driving the synthesis of RNA from DNA template molecules. In eukaryotes, a total of three RNA Pol enzymes generate the plethora of RNA species and RNA Pol II is the one transcribing all protein-coding genes. A high number of cis- and trans-acting factors orchestrates RNA Pol II-mediated transcription by influencing the chromatin recruitment, activation, elongation, and/or termination steps. The levels of DNA accessibility, defining open-euchromatin versus close-heterochromatin, delimits RNA Pol II activity as well as the encounter with other factors acting on chromatin such as the DNA replication or DNA repair machineries. The stage of the cell cycle highly influences RNA Pol II activity with mitosis representing the major challenge. In fact, there is a massive inhibition of transcription during the mitotic entry coupled with chromatin dissociation of most of the components of the transcriptional machinery. Mitosis, as a consequence, highly compromises the transcriptional memory and the perpetuation of cellular identity. Once mitosis ends, transcription levels immediately recover to define the cell fate and to safeguard the proper progression of daughter cells through the cell cycle. In this review, we evaluate our current understanding of the transcriptional repression associated with mitosis with a special focus on the molecular mechanisms involved, on the potential function behind the general repression, and on the transmission of the transcriptional machinery into the daughter cells. We finally discuss the contribution that errors in the inheritance of the transcriptional machinery across mitosis might play in stem cell aging.


Assuntos
Mitose , RNA Polimerase II , RNA Polimerase II/metabolismo , Transcrição Gênica , Cromatina , DNA , RNA
17.
BMC Plant Biol ; 24(1): 157, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38424498

RESUMO

BACKGROUND: D-type cyclins (CYCD) regulate the cell cycle G1/S transition and are thus closely involved in cell cycle progression. However, little is known about their functions in rice. RESULTS: We identified 14 CYCD genes in the rice genome and confirmed the presence of characteristic cyclin domains in each. The expression of the OsCYCD genes in different tissues was investigated. Most OsCYCD genes were expressed at least in one of the analyzed tissues, with varying degrees of expression. Ten OsCYCD proteins could interact with both retinoblastoma-related protein (RBR) and A-type cyclin-dependent kinases (CDKA) forming holistic complexes, while OsCYCD3;1, OsCYCD6;1, and OsCYCD7;1 bound only one component, and OsCYCD4;2 bound to neither protein. Interestingly, all OsCYCD genes except OsCYCD7;1, were able to induce tobacco pavement cells to re-enter mitosis with different efficiencies. Transgenic rice plants overexpressing OsCYCD2;2, OsCYCD6;1, and OsCYCD7;1 (which induced cell division in tobacco with high-, low-, and zero-efficiency, respectively) were created. Higher levels of cell division were observed in both the stomatal lineage and epidermal cells of the OsCYCD2;2- and OsCYCD6;1-overexpressing plants, with lower levels seen in OsCYCD7;1-overexpressing plants. CONCLUSIONS: The distinct expression patterns and varying effects on the cell cycle suggest different functions for the various OsCYCD proteins. Our findings will enhance understanding of the CYCD family in rice and provide a preliminary foundation for the future functional verification of these genes.


Assuntos
Ciclinas , Oryza , Ciclinas/genética , Ciclinas/metabolismo , Oryza/genética , Oryza/metabolismo , Fosforilação , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Ciclo Celular/genética , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Mitose
18.
Cell Mol Life Sci ; 81(1): 72, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300329

RESUMO

Hypoxia-inducible factor-1 (HIF-1) is the key transcriptional mediator of the cellular response to hypoxia and is also involved in cancer progression. Regulation of its oxygen-sensitive HIF-1α subunit involves post-translational modifications that control its stability, subcellular localization, and activity. We have previously reported that phosphorylation of the HIF-1α C-terminal domain by ERK1/2 promotes HIF-1α nuclear accumulation and stimulates HIF-1 activity while lack of this modification triggers HIF-1α nuclear export and its association with mitochondria. On the other hand, modification of the N-terminal domain of HIF-1α by CK1δ impairs HIF-1 activity by obstructing the formation of a HIF-1α/ARNT heterodimer. Investigation of these two antagonistic events by expressing double phospho-site mutants in HIF1A-/- cells under hypoxia revealed independent and additive phosphorylation effects that can create a gradient of HIF-1α subcellular localization and transcriptional activity. Furthermore, modification by CK1δ caused mitochondrial release of the non-nuclear HIF-1α form and binding to microtubules via its N-terminal domain. In agreement, endogenous HIF-1α could be shown to co-localize with mitotic spindle microtubules and interact with tubulin, both of which were inhibited by CK1δ silencing or inhibition. Moreover, CK1δ expression was necessary for equal partitioning of mother cell-produced HIF-1α to the daughter cell nuclei at the end of mitosis. Overall, our results suggest that phosphorylation by CK1δ stimulates the association of non-nuclear HIF-1α with microtubules, which may serve as a means to establish a symmetric distribution of HIF-1α during cell division under low oxygen conditions.


Assuntos
Sistema de Sinalização das MAP Quinases , Proteínas Quinases , Humanos , Mitose , Microtúbulos , Hipóxia , Oxigênio
19.
Biomed Phys Eng Express ; 10(2)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38357907

RESUMO

The assessment of mitotic activity is an integral part of the comprehensive evaluation of breast cancer pathology. Understanding the level of tumor dissemination is essential for assessing the severity of the malignancy and guiding appropriate treatment strategies. A pathologist must manually perform the intricate and time-consuming task of counting mitoses by examining biopsy slices stained with Hematoxylin and Eosin (H&E) under a microscope. Mitotic cells can be challenging to distinguish in H&E-stained sections due to limited available datasets and similarities among mitotic and non-mitotic cells. Computer-assisted mitosis detection approaches have simplified the whole procedure by selecting, detecting, and labeling mitotic cells. Traditional detection strategies rely on image processing techniques that apply custom criteria to distinguish between different aspects of an image. Additionally, the automatic feature extraction from histopathology images that exhibit mitosis using neural networks.Additionally, the possibility of automatically extracting features from histopathological images using deep neural networks was investigated. This study examines mitosis detection as an object detection problem using multiple neural networks. From a medical standpoint, mitosis at the tissue level was also investigated utilising pre-trained Faster R-CNN and raw image data. Experiments were done on the MITOS-ATYPIA- 14 dataset and TUPAC16 dataset, and the results were compared to those of other methods described in the literature.


Assuntos
Neoplasias da Mama , Mitose , Humanos , Feminino , Redes Neurais de Computação , Neoplasias da Mama/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos
20.
J Cell Sci ; 137(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38334041

RESUMO

Cells have evolved intricate mechanisms for dividing their contents in the most symmetric way during mitosis. However, a small proportion of cell divisions results in asymmetric segregation of cellular components, which leads to differences in the characteristics of daughter cells. Although the classical function of asymmetric cell division (ACD) in the regulation of pluripotency is the generation of one differentiated daughter cell and one self-renewing stem cell, recent evidence suggests that ACD plays a role in other physiological processes. In cancer, tumor heterogeneity can result from the asymmetric segregation of genetic material and other cellular components, resulting in cell-to-cell differences in fitness and response to therapy. Defining the contribution of ACD in generating differences in key features relevant to cancer biology is crucial to advancing our understanding of the causes of tumor heterogeneity and developing strategies to mitigate or counteract it. In this Review, we delve into the occurrence of asymmetric mitosis in cancer cells and consider how ACD contributes to the variability of several phenotypes. By synthesizing the current literature, we explore the molecular mechanisms underlying ACD, the implications of phenotypic heterogeneity in cancer, and the complex interplay between these two phenomena.


Assuntos
Divisão Celular Assimétrica , Neoplasias , Humanos , Mitose/genética , Neoplasias/genética , Células-Tronco , Diferenciação Celular
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