CCND1
G1/S-specific cyclin-D1 (B-cell lymphoma 1 protein) (BCL-1) (BCL-1 oncogene) (PRAD1 oncogene) [BCL1] [PRAD1]
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The objective of this study was to evaluate the ability of three distinct agents on the induction of senescence in human dental pulp stem cells (DPSCs). DPSCs from three separate donors were treated with H O , doxorubicin and ultraviolet (UV) irradiation. The response of the cells to the three agents was assayed by specific staining for SA-βGal, RT-qPCR and flow cytometry. The results showed that incubation with 100 μM H O and 20 nM Doxorubicin for seven days led to senescence in all donors' cells equally. Interestingly, UV irradiation for just one minute was sufficient to induce senescence in the cells. The SA-βGal positive senescent cells were arrested in G phase and their S phase was significantly reduced as analyzed by flow cytometry. Significant increment in p21 and BTG1 expression and decrement in CCND1 expression also confirmed the cells have been arrested and get senescent via p53-p21 pathway. All three agents successfully triggered senescence in the cells. There was no significant difference in the capacity of the three donor's cells for senescence. To avoid premature senescence in stem cell in vitro, it is recommended to avoid unnecessary exposure of the cell to fluorescent and UV light. Moreover, to prevent ROS production, we recommend using a separate incubator with low oxygen content for cell culture, if possible.
MeSH Terms
- Cells, Cultured
- Cellular Senescence
- Dental Pulp
- Doxorubicin
- Humans
- Hydrogen Peroxide
- Stem Cells
- Ultraviolet Rays
Keywords
- Cell cycle
- ROS
- Stress induced senescence
- Ultraviolet irradiation
- p21
Preclinical experiments and clinical trials demonstrated that angiotensin II AT receptor overactivity associates with aging and cellular senescence and that AT receptor blockers (ARBs) protect from age-related brain disorders. In a primary neuronal culture submitted to glutamate excitotoxicity, gene set enrichment analysis (GSEA) revealed expression of several hundred genes altered by glutamate and normalized by candesartan correlated with changes in expression in Alzheimer's patient's hippocampus. To further establish whether our data correlated with gene expression alterations associated with aging and senescence, we compared our global transcriptional data with additional published datasets, including alterations in gene expression in the neocortex and cerebellum of old mice, human frontal cortex after age of 40, gene alterations in the Werner syndrome, rodent caloric restriction, Ras and oncogene-induced senescence in fibroblasts, and to tissues besides the brain such as the muscle and kidney. The most significant and enriched pathways associated with aging and senescence were positively correlated with alterations in gene expression in glutamate-injured neurons and, conversely, negatively correlated when the injured neurons were treated with candesartan. Our results involve multiple genes and pathways, including CAV1, CCND1, CDKN1A, CHEK1, ICAM1, IL-1B, IL-6, MAPK14, PTGS2, SERPINE1, and TP53, encoding proteins associated with aging and senescence hallmarks, such as inflammation, oxidative stress, cell cycle and mitochondrial function alterations, insulin resistance, genomic instability including telomere shortening and DNA damage, and the senescent-associated secretory phenotype. Our results demonstrate that AT receptor blockade ameliorates central mechanisms of aging and senescence. Using ARBs for prevention and treatment of age-related disorders has important translational value.
Keywords
- Aging
- Angiotensin receptor blockers
- Glutamate excitotoxicity
- Senescence
- p53 neuroprotection
Multipotent mesenchymal stromal cells are considered as a perspective tool in cell therapy and regenerative medicine. Unfortunately, autologous cell therapy does not always provide positive outcomes in elder donors, perhaps as a result of the alterations of stem cell compartments. The mechanisms of stem and progenitor cell senescence and the factors engaged are investigated intensively. In present paper, we elucidated the effects of tissue-related O on morphology, functions, and transcriptomic profile of adipose tissue-derived stromal cells (ASCs) in replicative senescence in vitro model. Replicatively senescent ASCs at ambient (20%) O (12-21 passages) demonstrated an increased average cell size, granularity, reactive oxygen species level, including anion superoxide, lysosomal compartment activity, and IL-6 production. Decreased ASC viability and proliferation, as well as the change of more than 10 senescence-associated gene expression were detected (IGF1, CDKN1C, ID1, CCND1, etc). Long-term ASC expansion at low O (5%) revoked in part the replicative senescence-associated alterations.
MeSH Terms
- Adipose Tissue
- Cell Culture Techniques
- Cell Hypoxia
- Cells, Cultured
- Cellular Senescence
- Female
- Gene Expression Regulation
- Humans
- Male
- Mesenchymal Stem Cells
Keywords
- ASCs
- ROS
- functional state of organelles
- hypoxia
- paracrine activity
- senescence
- senescence-associated genes
Sporadic colorectal cancer (CRC) development is a sequential process showing age-dependency, uncontrolled epithelial proliferation and decreased apoptosis. During juvenile growth cellular proliferation and apoptosis are well balanced, which may be perturbed upon aging. Our aim was to correlate proliferative and apoptotic activities in aging human colonic epithelium and colorectal cancer. We also tested the underlying molecular biology concerning the proliferation- and apoptosis-regulating gene expression alterations. Colorectal biopsies from healthy children (n1 = 14), healthy adults (n2 = 10), adult adenomas (n3 = 10) and CRCs (n4 = 10) in adults were tested for Ki-67 immunohistochemistry and TUNEL apoptosis assay. Mitosis- and apoptosis-related gene expression was also studied in healthy children (n1 = 6), adult (n2 = 41) samples and in CRC (n3 = 34) in HGU133plus2.0 microarray platform. Measured alterations were confirmed with RT-PCR both on dependent and independent sample sets (n1 = 6, n2 = 6, n3 = 6). Mitotic index (MI) was significantly higher (p<0.05) in intact juvenile (MI = 0.33±0.06) and CRC samples (MI = 0.42±0.10) compared to healthy adult samples (MI = 0.15±0.06). In contrast, apoptotic index (AI) was decreased in children (0.13±0.06) and significantly lower in cancer (0.06±0.03) compared to healthy adult samples (0.17±0.05). Eight proliferation- (e.g. MKI67, CCNE1) and 11 apoptosis-associated genes (e.g. TNFSF10, IFI6) had altered mRNA expression both in the course of normal aging and carcinogenesis, mainly inducing proliferation and reducing apoptosis compared to healthy adults. Eight proliferation-associated genes including CCND1, CDK1, CDK6 and 26 apoptosis-regulating genes (e.g. SOCS3) were differently expressed between juvenile and cancer groups mostly supporting the pronounced cell growth in CRC. Colorectal samples from children and CRC patients can be characterized by similarly increased proliferative and decreased apoptotic activities compared to healthy colonic samples from adults. Therefore, cell kinetic alterations during colorectal cancer development show uncontrolled rejuvenescence as opposed to the controlled cell growth in juvenile colonic epithelium.
MeSH Terms
- Adult
- Aging
- Apoptosis
- Carcinogenesis
- Cell Proliferation
- Child
- Colorectal Neoplasms
- Female
- Gene Expression Profiling
- Humans
- Intestinal Mucosa
- Male
Microarray gene expression data were used to analyze the expression pattern of cyclin, cyclin-dependent kinase (CDKs) and cyclin-dependent kinase inhibitor (CDKIs) genes from human pancreatic islets with and without type 2 diabetes (T2D). Of the cyclin genes, CCNI was the most expressed. Data obtained from microarray and qRT-PCR showed higher expression of CCND1 in diabetic islets. Among the CDKs, CDK4, CDK8 and CDK9 were highly expressed, while CDK1 was expressed at low level. High expression of [[CDK18]] was observed in diabetic islets. Of the CDKIs, CDKN1A expression was higher in diabetic islets in both microarray and qRT-PCR. Expression of CDKN1A, [[CDKN2A]], CCNI2, CDK3 and CDK16 was correlated with age. Finally, eight SNPs in these genes were associated with T2D in the DIAGRAM database. Our data provide a comprehensive expression pattern of cell cycle genes in human islets. More human studies are required to confirm and reproduce animal studies.
MeSH Terms
- Aged
- Aging
- Case-Control Studies
- Cells, Cultured
- Cyclin-Dependent Kinase Inhibitor Proteins
- Cyclin-Dependent Kinases
- Cyclins
- Diabetes Mellitus, Type 2
- Female
- Gene Expression Profiling
- Genes, cdc
- Genetic Association Studies
- Genetic Predisposition to Disease
- Humans
- Insulin
- Insulin Secretion
- Islets of Langerhans
- Male
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- Polymorphism, Single Nucleotide
- Transcriptome