Multifaceted Microcephaly-Related Gene MCPH1

MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its dysfunction in regulating the proliferation and self-renewal of neuroprogenitor cells. In the last 20 years or so, genetic and cellular studies have identified MCPH1 as a multifaceted protein in various cellular functions, including DNA damage signaling and repair, the regulation of chromosome condensation, cell-cycle progression, centrosome activity and the metabolism. Yet, genetic and animal model studies have revealed an unpredicted essential function of MPCH1 in gonad development and tumorigenesis, although the underlying mechanism remains elusive. These studies have begun to shed light on the role of MPCH1 in controlling various pathobiological processes of the disorder. Here, we summarize the biological functions of MCPH1, and lessons learnt from cellular and mouse models of MCPH1.

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The N-terminal BRCT domain determines MCPH1 function in brain development and fertility

Cell Death and Disease ◽

10.1038/s41419-021-03406-3 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Xiaoqian Liu ◽

Nadine Schneble-Löhnert ◽

Martina Kristofova ◽

Xiaobing Qing ◽

Jan Labisch ◽

...

Keyword(s):

Brain Size ◽

Neurodevelopmental Disorder ◽

Gonad Development ◽

Brct Domain ◽

Primary Microcephaly ◽

Cellular Processes ◽

Damage Response ◽

Almost All

AbstractMCPH1 is a causal gene for the neurodevelopmental disorder, human primary microcephaly (MCPH1, OMIM251200). Most pathogenic mutations are located in the N-terminal region of the gene, which encodes a BRCT domain, suggesting an important function of this domain in brain size determination. To investigate the specific function of the N-terminal BRCT domain in vivo, we generated a mouse model lacking the N’-BRCT domain of MCPH1 (referred as Mcph1-ΔBR1). These mutant mice are viable, but exhibit reduced brain size, with a thinner cortex due to a reduction of neuroprogenitor populations and premature neurogenic differentiation. Mcph1-ΔBR1 mice (both male and female) are infertile; however, almost all female mutants develop ovary tumours. Mcph1-ΔBR1 MEF cells exhibit a defect in DNA damage response and DNA repair, and show the premature chromosome condensation (PCC) phenotype, a hallmark of MCPH1 patient cells and also Mcph1 knockout cells. In comparison with Mcph1 complete knockout mice, Mcph1-ΔBR1 mice faithfully reproduce all phenotypes, indicating an essential role of the N-terminal BRCT domain for the physiological function of MCPH1 in the control of brain size and gonad development as well as in multiple cellular processes.

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The role of SOX18 in bladder cancer and its underlying mechanism in mediating cellular functions

Life Sciences ◽

10.1016/j.lfs.2019.116614 ◽

2019 ◽

Vol 232 ◽

pp. 116614

Author(s):

Yin Huaqi ◽

Qin Caipeng ◽

Wang Qiang ◽

Du Yiqing ◽

Xu Tao

Keyword(s):

Bladder Cancer ◽

Underlying Mechanism ◽

Cellular Functions

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The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies

Immunology Letters ◽

10.1016/j.imlet.2008.03.002 ◽

2008 ◽

Vol 118 (1) ◽

pp. 1-5 ◽

Cited By ~ 27

Author(s):

Dimitry A. Chistiakov ◽

Natalia V. Voronova ◽

Pavel A. Chistiakov

Keyword(s):

Animal Model ◽

Type 1 Diabetes ◽

Immune Regulation ◽

Crucial Role ◽

Model Studies

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B Cells in Autoimmune Diseases

Scientifica ◽

10.6064/2012/215308 ◽

2012 ◽

Vol 2012 ◽

pp. 1-18 ◽

Cited By ~ 45

Author(s):

Christiane S. Hampe

Keyword(s):

B Cells ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Germinal Centers ◽

Cellular Functions ◽

Systemic Lupus ◽

Reciprocal Interactions ◽

Selective Targeting

The role of B cells in autoimmune diseases involves different cellular functions, including the well-established secretion of autoantibodies, autoantigen presentation and ensuing reciprocal interactions with T cells, secretion of inflammatory cytokines, and the generation of ectopic germinal centers. Through these mechanisms B cells are involved both in autoimmune diseases that are traditionally viewed as antibody mediated and also in autoimmune diseases that are commonly classified as T cell mediated. This new understanding of the role of B cells opened up novel therapeutic options for the treatment of autoimmune diseases. This paper includes an overview of the different functions of B cells in autoimmunity; the involvement of B cells in systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes; and current B-cell-based therapeutic treatments. We conclude with a discussion of novel therapies aimed at the selective targeting of pathogenic B cells.

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CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response

The Journal of Cell Biology ◽

10.1083/jcb.200912163 ◽

2010 ◽

Vol 189 (1) ◽

pp. 23-39 ◽

Cited By ~ 77

Author(s):

Alexis R. Barr ◽

John V. Kilmartin ◽

Fanni Gergely

Keyword(s):

Dna Damage ◽

Cell Fate ◽

Mitotic Spindle ◽

Brain Size ◽

Neurodevelopmental Disorder ◽

Spindle Pole ◽

Spindle Positioning ◽

Dna Damage Signaling ◽

Spindle Poles ◽

G2 Cell Cycle Arrest

The centrosomal protein, CDK5RAP2, is mutated in primary microcephaly, a neurodevelopmental disorder characterized by reduced brain size. The Drosophila melanogaster homologue of CDK5RAP2, centrosomin (Cnn), maintains the pericentriolar matrix (PCM) around centrioles during mitosis. In this study, we demonstrate a similar role for CDK5RAP2 in vertebrate cells. By disrupting two evolutionarily conserved domains of CDK5RAP2, CNN1 and CNN2, in the avian B cell line DT40, we find that both domains are essential for linking centrosomes to mitotic spindle poles. Although structurally intact, centrosomes lacking the CNN1 domain fail to recruit specific PCM components that mediate attachment to spindle poles. Furthermore, we show that the CNN1 domain enforces cohesion between parental centrioles during interphase and promotes efficient DNA damage–induced G2 cell cycle arrest. Because mitotic spindle positioning, asymmetric centrosome inheritance, and DNA damage signaling have all been implicated in cell fate determination during neurogenesis, our findings provide novel insight into how impaired CDK5RAP2 function could cause premature depletion of neural stem cells and thereby microcephaly.

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Essence of PTEN: a Broad-Spectrum Therapeutic Target in Cancer

Biointerface Research in Applied Chemistry ◽

10.33263/briac112.95879603 ◽

2020 ◽

Vol 11 (2) ◽

pp. 9587-9603

Keyword(s):

Tumor Suppressor ◽

Tyrosine Kinases ◽

Cell Cycle Progression ◽

Protein Tyrosine Phosphatases ◽

Underlying Mechanism ◽

Pten Gene ◽

Tyrosine Phosphatases ◽

Protein Tyrosine ◽

Tensin Homolog

The levels of protein tyrosine phosphorylation within a cell is regulated by protein tyrosine kinases and protein tyrosine phosphatases. These protein tyrosine phosphatases (PTP) can act both as positive and negative regulators during cell cycle progression and signal transduction. Phosphatase activity is shown by Phosphatase and Tensin homolog (PTEN) protein encoded by PTEN gene localized on human chromosome 10. Earlier findings established the role of PTEN as a tumor suppressor in Cowden’s disease, where PTEN mutations resulted in disease outcomes. Subsequent studies found the role of PTEN mutations in various human cancers, making it one of the vastly studied tumor suppressor genes. The current review has been planned to get a deeper insight into the potential role of PTEN in a variety of physiological processes involved in normal development like cell growth, migration, and differentiation along with the factors, regulation, and underlying mechanism.

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High Iodine Induces the Proliferation of Papillary and Anaplastic Thyroid Cancer Cells via AKT/Wee1/CDK1 Axis

Frontiers in Oncology ◽

10.3389/fonc.2021.622085 ◽

2021 ◽

Vol 11 ◽

Author(s):

Chunpeng Lv ◽

Yanhui Gao ◽

Jinyin Yao ◽

Yan Li ◽

Qun Lou ◽

...

Keyword(s):

Cell Cycle ◽

Thyroid Cancer ◽

Cancer Cells ◽

Cell Cycle Progression ◽

Anaplastic Thyroid Cancer ◽

Underlying Mechanism ◽

High Iodine ◽

Akt Phosphorylation ◽

Thyroid Cancer Cells

High iodine can alter the proliferative activity of thyroid cancer cells, but the underlying mechanism has not been fully elucidated. Here, the role of high iodine in the proliferation of thyroid cancer cells was studied. In this study, we demonstrated that high iodine induced the proliferation of BCPAP and 8305C cells via accelerating cell cycle progression. The transcriptome analysis showed that there were 295 differentially expressed genes (DEGs) in BCPAP and 8305C cells induced by high iodine, among which CDK1 expression associated with the proliferation of thyroid cancer cells induced by high iodine. Moreover, the western blot analysis revealed that cells exposed to high iodine enhanced the phosphorylation activation of AKT and the expression of phospho-Wee1 (Ser642), while decreasing the expression of phospho-CDK1 (Tyr15). Importantly, the inhibition of AKT phosphorylation revered the expression of CDK1 induced by high iodine and arrested the cell cycle in the G1 phase, decreasing the proliferation of thyroid cancer cells induced by high iodine. Taken together, these findings suggested that high iodine induced the proliferation of thyroid cancer cells through AKT-mediated Wee1/CDK1 axis, which provided new insights into the regulation of proliferation of thyroid cancer cells by iodine.

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HPV-positive head and neck cancer derived exosomal miR-9 induces M1 macrophage polarization and increases tumor radiosensitivity

10.1101/820282 ◽

2019 ◽

Author(s):

Fangjia Tong ◽

Siwei Zhang ◽

Huanhuan Xie ◽

Bingqing Yan ◽

Lianhao Song ◽

...

Keyword(s):

Tumor Microenvironment ◽

Head And Neck ◽

Macrophage Polarization ◽

Underlying Mechanism ◽

Radiation Sensitivity ◽

Cellular Functions ◽

M1 Macrophages ◽

M1 Macrophage ◽

M1 Phenotype

AbstractHuman papillomavirus (HPV) is an etiological risk factor for a subset of head and neck squamous cell carcinoma (HNSCC). HPV+ HNSCC is significant more radiosensitive than HPV-HNSCC, but the underlying mechanism is still unknown. Tumor microenvironment can affect tumor response to radiation therapy. Cancer secreted exosomes are emerging as crosstalk mediators between tumor cells and the tumor microenvironment. The main objectives of this study were to determine the role of HPV+ HNSCC-derived exosomes in increased radiation sensitivity. Here, we found that exosomes derived from HPV+ HNSCC cells activate macrophages into the M1 phenotype, which then increases the radiosensitivity of HNSCC cells. miR-9 was enriched in exosomes released from HPV+ HNSCC cells and it could be transported to macrophages, leading to altered cellular functions. Overexpression of miR-9 in macrophages induced polarization into the M1 phenotype via downregulation of PPARδ. Increased radiosensitivity was observed for HNSCC cells co-cultured with macrophages in which miR-9 was upregulated or treated with M1 macrophages. These observations suggest that HPV+ HNSCC cells secrete miR-9-rich exosomes, which then polarize macrophages into M1 phenotype and lead to increased radiosensitivity of HNSCC cells. Hence, miR-9 may be a potential treatment strategy for HNSCC.Statement of significanceHPV+ HNSCC through the release of miR-9-rich exosomes polarize macrophages into M1 phenotype and lead to increased radiosensitivity of HNSCC.

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Molecular and Cellular Basis of Autosomal Recessive Primary Microcephaly

BioMed Research International ◽

10.1155/2014/547986 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 49

Author(s):

Marine Barbelanne ◽

William Y. Tsang

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Autosomal Recessive ◽

Brain Size ◽

Neurodevelopmental Disorder ◽

Primary Microcephaly ◽

Cycle Progression ◽

Early Brain Development ◽

Cycle Regulation ◽

Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development.

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