CDC42
Cell division control protein 42 homolog precursor (EC 3.6.5.2) (G25K GTP-binding protein)
Publications[править]
Angiogenesis - the growth of new blood capillaries- is impaired in aging animals. Biophysical factors such as changes in cell size control endothelial cell (EC) proliferation and differentiation. However, the effects of aging on EC size and the mechanism by which changes in cell size control age-dependent decline in EC proliferation are largely unknown. Here, we have demonstrated that aged ECs are larger than young ECs and that age-dependent increases in EC size control EC proliferation and senescence through CDC42-Yes-associated protein (YAP1) signaling. Reduction of aged EC size by culturing on single-cell sized fibronectin-coated smaller islands decreases CDC42 activity, stimulates YAP1 nuclear translocation and attenuates EC senescence. Stimulation of YAP1 or inhibition of CDC42 activity in aged ECs also restores blood vessel formation. Age-dependent changes in EC size and/or CDC42 and YAP1 activity may be the key control point of age-related decline in angiogenesis.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adult
- Aging
- Animals
- Cell Cycle Proteins
- Cell Size
- Endothelial Cells
- Female
- Humans
- Male
- Mice, Inbred C57BL
- Middle Aged
- Neovascularization, Physiologic
- Primary Cell Culture
- Transcription Factors
- cdc42 GTP-Binding Protein
Keywords
- aging
- angiogenesis
- cell proliferation
- cell size
- senescence
Frontal cortical dysfunction is a fundamental pathology contributing to age-associated behavioral and cognitive deficits that predispose older adults to neurodegenerative diseases. It is established that aging increases the risk of frontal cortical dysfunction; however, the underlying molecular mechanism remains elusive. Here, we used an integrative meta-analysis to combine five frontal cortex microarray studies with a combined sample population of 161 younger and 155 older individuals. A network-based analysis was used to describe an outline of human frontal cortical aging to identify core genes whose expression changes with age and to reveal the interrelationships among these genes. We found that [i]histone deacetylase 1[/i] ([i]HDAC1[/i]) and [i]YES proto-oncogene 1[/i] ([i]YES1[/i]) are the two most upregulated genes, while [i]cell division cycle 42[/i] ([i]CDC42[/i]) is the central regulatory gene decreased in the aged human frontal cortex. Quantitative PCR assays revealed corresponding changes in frontal cortical Hdac1, Yes1 and Cdc42 mRNA levels in an established aging mouse model. Moreover, analysis of the GSE48350 dataset confirmed similar changes in HDAC1, CDC42 and YES1 expression in Alzheimer's disease, thereby providing a molecular connection between aging and Alzheimer's disease (AD). This framework of network-based analysis could provide novel strategies for detecting and monitoring aging in the brain.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Animals
- Behavior, Animal
- Frontal Lobe
- Gene Expression Profiling
- Gene Regulatory Networks
- Histone Deacetylase 1
- Humans
- Maze Learning
- Mice, Inbred C57BL
- Middle Aged
- Models, Animal
- Network Meta-Analysis
- Oligonucleotide Array Sequence Analysis
- Proto-Oncogene Proteins c-yes
- RNA, Messenger
- Transcriptome
- Young Adult
- cdc42 GTP-Binding Protein
Keywords
- CDC42
- HDAC1
- YES1
- frontal cortex aging
- network-based analysis
The biochemical ageing status of women in the menopausal transition was studied using quantitative analysis of age- and autophagy-related gene activities (CDC42 and MAP1LC3 genes were selected as target genes). Free estradiol and progesterone levels in saliva were estimated. General linear models were used to determine the relationship between lifestyle, health status, socioeconomic factors and CDC42 and MAP1LC3 gene expression levels. Gene expression analysis revealed (1) an increasing expression of CDC42 gene after 45years in women, (2) expression level of CDC42 gene associated with menopausal status, (3) while endocrine status was found to associate with the expression of both of the studied age-related genes, (4) the "never used hormonal contraceptives" and "obese nutritional status" were the strongest factors for increased level of age-related gene expressions, and (5) changes in gene expression levels by ageing should be studied by considering not only chronological, but also biological ages. Gene expression profile of ageing has mostly been studied in model systems or human blood samples, but rarely in human saliva samples. The concordance of results between the present and former gene expression analyses, and the simplicity of saliva sample collection emphasizes the importance of saliva tissue samples in gene expression analyses especially in epidemiological surveys.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Estradiol
- Female
- Gene Expression Regulation
- Health Status
- Humans
- Hungary
- Life Style
- Linear Models
- Menopause
- Microtubule-Associated Proteins
- Middle Aged
- Progesterone
- Reproduction
- Saliva
- Socioeconomic Factors
- cdc42 GTP-Binding Protein
Keywords
- Ageing
- Biometric, lifestyle and socioeconomic factors
- CDC42 and MAP1LC3 gene activity
- Menopausal transition
- Salivary RNA
Mammalian cells mostly rely on extracellular molecules to transfer signals to other cells. However, in stress conditions, more robust mechanisms might be necessary to facilitate cell-cell communications. Cellular senescence, a stress response associated with permanent exit from the cell cycle and the development of an immunogenic phenotype, limits both tumorigenesis and tissue damage. Paradoxically, the long-term presence of senescent cells can promote tissue damage and aging within their microenvironment. Soluble factors secreted from senescent cells mediate some of these cell-nonautonomous effects. However, it is unknown whether senescent cells impact neighboring cells by other mechanisms. Here we show that senescent cells directly transfer proteins to neighboring cells and that this process facilitates immune surveillance of senescent cells by natural killer (NK) cells. We found that transfer of proteins to NK and T cells is increased in the murine preneoplastic pancreas, a site where senescent cells are present in vivo. Proteomic analysis and functional studies of the transferred proteins revealed that the transfer is strictly dependent on cell-cell contact and CDC42-regulated actin polymerization and is mediated at least partially by cytoplasmic bridges. These findings reveal a novel mode of intercellular communication by which senescent cells regulate their immune surveillance and might impact tumorigenesis and tissue aging.
MeSH Terms
- Actins
- Animals
- Cell Communication
- Cellular Senescence
- Fibroblasts
- Killer Cells, Natural
- Lymphocyte Activation
- Mice
- Pancreas
- Polymerization
- Protein Transport
- T-Lymphocytes
- rho GTP-Binding Proteins
Keywords
- actin polymerization
- cellular senescence
- cytoplasmic bridges
- natural killer cells
Risk factors for atherosclerosis accelerate the senescence of vascular endothelial cells and promote atherogenesis by inducing vascular inflammation. A hallmark of endothelial senescence is the persistent up-regulation of pro-inflammatory genes. We identified CDC42 signaling as a mediator of chronic inflammation associated with endothelial senescence. Inhibition of CDC42 or NF-κB signaling attenuated the sustained up-regulation of pro-inflammatory genes in senescent human endothelial cells. Endothelium-specific activation of the p53/p21 pathway, a key mediator of senescence, also resulted in up-regulation of pro-inflammatory molecules in mice, which was reversed by Cdc42 deletion in endothelial cells. Likewise, endothelial-specific deletion of Cdc42 significantly attenuated chronic inflammation and plaque formation in atherosclerotic mice. While inhibition of NF-κB suppressed the pro-inflammatory responses in acute inflammation, the influence of Cdc42 deletion was less marked. Knockdown of cdc-42 significantly down-regulated pro-inflammatory gene expression and restored the shortened lifespan to normal in mutant worms with enhanced inflammation. These findings indicate that the CDC42 pathway is critically involved in senescence-associated inflammation and could be a therapeutic target for chronic inflammation in patients with age-related diseases without compromising host defenses.
MeSH Terms
- Animals
- Atherosclerosis
- Caenorhabditis elegans
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p21
- Endothelial Cells
- Endothelium, Vascular
- Gene Expression Regulation
- Humans
- Inflammation
- Longevity
- Mice
- Mice, Transgenic
- NF-kappa B
- RNA, Small Interfering
- Signal Transduction
- Tumor Suppressor Protein p53
- cdc42 GTP-Binding Protein
Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is one of the most important receptors for binding and uptake of ox-LDL in endothelial cells, vascular smooth muscle cells and cardiomyocytes. In this study in cultured mice heart fibroblasts, we describe a decrease in LOX-1 expression as these cells go through successive passages. Further, fibroblast aging is associated with significant changes in morphology and proliferation ability. The same phenomena were observed in primary cardiac fibroblasts isolated from the aged mice (130-week). We also noted that the senescent fibroblasts have increased susceptibility to apoptosis and have a disorganized cytoskeleton. To ascertain the contribution of LOX-1 in the decline in proliferative ability and morphological changes in the aged cells, senescent fibroblasts were transfected with h-LOX-1. Transfection with h-LOX-1 resulted in cytoskeleton reorganization and partial restoration of the expression of related proteins, CDC42 and p70 S6 kinase. Upregulation of LOX-1 also significantly enhanced their proliferation potential and restored the expression of related genes Mdm2 and phos-Akt, and modestly reduced the expression of aging markers 4-HNE and β-catenin. These findings suggest that LOX-1 contributes, at least in part, to the process of fibroblast senescence and may be viewed as a new aging maker.
MeSH Terms
- Aging
- Animals
- Biomarkers
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- Cytoskeleton
- Fibroblasts
- Mice
- Muscle Proteins
- Myocardium
- Scavenger Receptors, Class E
We investigated the hypothesis that gene expression profiles in cultured cell lines from adults, aged 57-97 years, contain information about the biological age and potential longevity of the donors. We studied 104 unrelated grandparents from 31 Utah CEU (Centre d'Etude du Polymorphisme Humain - Utah) families, for whom lymphoblastoid cell lines were established in the 1980s. Combining publicly available gene expression data from these cell lines, and survival data from the Utah Population Database, we tested the relationship between expression of 2151 always-expressed genes, age, and survival of the donors. Approximately 16% of 2151 expression levels were associated with donor age: 10% decreased in expression with age, and 6% increased with age. Cell division cycle 42 (CDC42) and CORO1A exhibited strong associations both with age at draw and survival after draw (multiple comparisons-adjusted Monte Carlo P-value < 0.05). In general, gene expressions that increased with age were associated with increased mortality. Gene expressions that decreased with age were generally associated with reduced mortality. A multivariate estimate of biological age modeled from expression data was dominated by CDC42 expression, and was a significant predictor of survival after blood draw. A multivariate model of survival as a function of gene expression was dominated by CORO1A expression. This model accounted for approximately 23% of the variation in survival among the CEU grandparents. Some expression levels were negligibly associated with age in this cross-sectional dataset, but strongly associated with inter-individual differences in survival. These observations may lead to new insights regarding the genetic contribution to exceptional longevity.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cell Line
- Environmental Exposure
- Gene Expression
- Gene Expression Profiling
- Humans
- Longevity
- Middle Aged
- Mortality
- Multivariate Analysis
- Proportional Hazards Models
Expression levels of 33 high egg production candidate transcripts in Red-feather Taiwan country chickens (TCCs) were examined by quantitative reverse-transcription (RT) polymerase chain reactions (PCR) in this study. Candidate transcripts were previously identified from a L2-B (L2-subtract-B) hypothalamus/pituitary gland subtractive cDNA library. In this subtractive cDNA library, two divergently selected strains of TCCs, B and L2 were used. These two strains were originated from one single population and were further subjected (since 1982) to the selections of body weight/comb size (B) and eggs to 40wk of age (L2), respectively. Hypothalamuses and pituitary glands that sampled from Red-feather TCCs were previously grouped into high (Red-high; n=20) and low (Red-low; n=20) egg productions based on the rate of lay after 1st egg (hen-day laying rate; %). Rates of lay after 1st egg (mean /-S.E.) in the Red-high and the Red-low subpopulations were 72.2 /-0.6 and 23.0 /-3.5, respectively (P<0.01). Quantitative RT-PCR validated that 25 candidate transcripts were significantly higher expressed in the Red-high than in the Red-low hens. These transcripts were ANP32A, BDH, CDC42, CNTN1, COMT, CPE, CTNNB1, DIO2, EIF4E, GARNL1, HSPCA, LAPTM4B, MBP, NAP1L4, NCAM1, PARK7, PCDHA@, PGDS, PLAG1, PRL, RAD21, SAR1A, SCG2, STMN1 and UFM1. Among these transcripts, 15 (79.0%), 13 (68.4%), and 12 (63.2%) genes were annotated to involve in cellular physiological process (GO:0050875), metabolism (GO:0008152) and cell communication (GO:0007154). Identified transcripts that related to high egg production are most active in focal adhesion, adherens junction, MAPK signaling, tight junction and cell adhesion pathways.
MeSH Terms
- Aging
- Animals
- Chickens
- Color
- Feathers
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Hypothalamus
- Oviposition
- Pituitary Gland
- Taiwan
- Transcription, Genetic