DUSP16

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Dual specificity protein phosphatase 16 (EC 3.1.3.16) (EC 3.1.3.48) (Mitogen-activated protein kinase phosphatase 7) (MAP kinase phosphatase 7) (MKP-7) [KIAA1700] [MKP7]

Publications[править]

Identifying blood-specific age-related DNA methylation markers on the Illumina MethylationEPIC® BeadChip.

The past decade has seen rapid development in DNA methylation (DNAm) microarrays, including the Illumina HumanMethylation27 and HumanMethylation450 (450K) chips, which have played an essential role in identifying and evaluating age-related (AR) DNAm markers in different tissues. Recently, a new array, the Illumina MethylationEPIC (EPIC) was introduced, with nearly double the number of probes as the 450K (∼850,000 probes). In this study, we test these newly added probes for age association using a large cohort of 754 DNAm profiles from blood samples assayed on the EPIC BeadChip, for individuals aged 0-88 years old. 52 AR CpG sites (Spearman's abs(rho) >0.6 and P-value <10 ) were identified, 21 of which were novel sites and mapped to 18 genes, nine of which (LHFPL4, SLC12A8, EGFEM1P, GPR158, TAL1, KIAA1755, LOC730668, DUSP16, and FAM65C) have never previously been reported to be associated with age. The data were subsequently split into a 527-sample training set and a 227-sample testing set to build and validate two age prediction models using elastic net regression and multivariate regression. Elastic net regression selected 425 CpG markers with a mean absolute deviation (MAD) of 2.6 years based on the testing set. To build a multivariate linear regression model, AR CpG sites with R > 0.5 at FDR < 0.05 were input into stepwise regression to select the best subset for age prediction. The resulting six CpG markers were linearly modelled with age and explained 81% of age-correlated variation in DNAm levels. Age estimation accuracy using bootstrap analysis was 4.5 years, with 95% confidence intervals of 4.56 to 4.57 years based on the testing set. These results suggest that EPIC BeadChip probes for age estimation fall within the range of probes found on the previous Illumina HumanMethylation platforms in terms of their age-prediction ability.

MeSH Terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging
  • Child
  • Child, Preschool
  • Cohort Studies
  • CpG Islands
  • DNA Methylation
  • Forensic Genetics
  • Genetic Markers
  • Humans
  • Infant
  • Infant, Newborn
  • Linear Models
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Young Adult

Keywords

  • Age
  • CpG sites
  • DNA methylation
  • Forensic age estimation
  • Forensic epigenetics
  • Illumina MethylationEPIC


Nicotinamide Mononucleotide, an NAD Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1-Dependent Manner.

The rapid growth of an aging population creates challenges regarding age-related diseases, including AKI, for which both the prevalence and death rate increase with age. The molecular mechanism by which the aged kidney becomes more susceptible to acute injury has not been completely elucidated. In this study, we found that, compared with the kidneys of 3-month-old mice, the kidneys of 20-month-old mice expressed reduced levels of the renal protective molecule sirtuin 1 (SIRT1) and its cofactor NAD Supplementation with nicotinamide mononucleotide (NMN), an NAD precursor, restored renal SIRT1 activity and NAD content in 20-month-old mice and further increased both in 3-month-old mice. Moreover, supplementation with NMN significantly protected mice in both age groups from cisplatin-induced AKI. SIRT1 deficiency blunted the protective effect of NMN, and microarray data revealed that c-Jun N-terminal kinase (JNK) signaling activation associated with renal injury in SIRT1 heterozygotes. [i]In vitro[/i], SIRT1 attenuated the stress response by modulating the JNK signaling pathway, probably [i]via[/i] the deacetylation of a JNK phosphatase, DUSP16. Taken together, our findings reveal SIRT1 as a crucial mediator in the renal aging process. Furthermore, manipulation of SIRT1 activity by NMN seems to be a potential pharmaceutical intervention for AKI that could contribute to the precise treatment of aged patients with AKI.

MeSH Terms

  • Acute Kidney Injury
  • Age Factors
  • Animals
  • Disease Susceptibility
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • NAD
  • Nicotinamide Mononucleotide
  • Sirtuin 1

Keywords

  • AKI
  • Aging
  • NAD
  • NMN
  • SIRT1
  • cisplatin nephrotoxicity


DUSP16 ablation arrests the cell cycle and induces cellular senescence.

Dual-specificity phosphatases (DUSPs) are a family of protein phosphatases that dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues. DUSPs are de-regulated in many human diseases, including cancers. However, the function of DUSPs in tumorigenesis remains largely unknown. Here, using short hairpin RNA-based gene knockdown, we found that several members of the DUSP family play critical roles in regulating cell proliferation. In particular, we showed that DUSP16 ablation leads to a G1/S transition arrest, reduced incorporation of 5-bromodeoxyuridine, enhanced senescence-associated β-galactosidase activity, and formation of senescence-associated heterochromatic foci. Mechanistically, DUSP16 silencing causes cellular senescence by activating the tumor suppressors p53 and Rb. The phosphatase activity of DUSP16 is necessary for antagonizing cellular senescence. Importantly, the expression levels of DUSP16 are up-regulated in human liver cancers, and are positively correlated with tumor cell proliferation. Taken together, our findings indicate that DUSP16 plays a role in tumorigenesis by protecting cancer cells from senescence.

MeSH Terms

  • Cell Cycle Checkpoints
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence
  • Dual-Specificity Phosphatases
  • Gene Silencing
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms
  • Mitogen-Activated Protein Kinase Phosphatases

Keywords

  • DUSP16
  • Rb
  • liver cancer
  • p53
  • senescence