Intracellular Insulin-like growth factor binding protein 2 (IGFBP2) contributes to the senescence of keratinocytes in psoriasis by stabilizing cytoplasmic p21

Mercurio, Laura; Lulli, Daniela; Mascia, Francesca; Dellambra, Elena; Scarponi, Claudia; Morelli, Martina; Valente, Carola; Carbone, Maria Luigia; Pallotta, Sabatino; Girolomoni, Giampiero; Albanesi, Cristina; Pastore, Saveria; Madonna, Stefania

doi:10.18632/aging.103045

Cited by 25 publications

(24 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we were able to detect significant differences between the DNAm age of healthy and AK samples as well as significant differences in psoriatic and cSCC samples. Nevertheless, our observation of a decrease in the mDNA age of psoriatic samples compared to normal counterparts disagrees with previously published data describing that psoriatic lesions are characterized by the presence of senescent keratinocytes, mainly observed in the mid and upper epidermal layers [ 42 ]. The keratinocytes derived from psoriatic diseases have already been shown to express high levels of CDKN2 ( P16 ), CDKN1A ( P21 ), as well as low CDK1 and CCNA1 , in addition to IGFBP2 [ 42 ], which is a component of SASP [ 43 ].…”

Section: Discussioncontrasting

confidence: 99%

Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging

Boroni

Zonari²,

Oliveira³

et al. 2020

Clin Epigenet

View full text Add to dashboard Cite

Background DNA methylation (DNAm) age constitutes a powerful tool to assess the molecular age and overall health status of biological samples. Recently, it has been shown that tissue-specific DNAm age predictors may present superior performance compared to the pan- or multi-tissue counterparts. The skin is the largest organ in the body and bears important roles, such as body temperature control, barrier function, and protection from external insults. As a consequence of the constant and intimate interaction between the skin and the environment, current DNAm estimators, routinely trained using internal tissues which are influenced by other stimuli, are mostly inadequate to accurately predict skin DNAm age. Results In the present study, we developed a highly accurate skin-specific DNAm age predictor, using DNAm data obtained from 508 human skin samples. Based on the analysis of 2,266 CpG sites, we accurately calculated the DNAm age of cultured skin cells and human skin biopsies. Age estimation was sensitive to the biological age of the donor, cell passage, skin disease status, as well as treatment with senotherapeutic drugs. Conclusions This highly accurate skin-specific DNAm age predictor constitutes a holistic tool that will be of great use in the analysis of human skin health status/molecular aging, as well as in the analysis of the potential of established and novel compounds to alter DNAm age.

show abstract

Section: Discussioncontrasting

confidence: 99%

Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging

Boroni

Zonari²,

Oliveira³

et al. 2020

Clin Epigenet

View full text Add to dashboard Cite

show abstract

“…AKT can also prevent cytokine-induced cellular apoptosis and promote senescence-like growth arrest in psoriasis (53) (Figure 1B). Indeed, psoriatic keratinocytes exhibit a senescent phenotype characterized by a peculiar resistance to apoptosis, secretion of inflammatory molecules, and expression of specific markers of senescence, which contributes to the epidermal thickening typically observed in psoriatic skin (106)(107)(108). Interestingly, the chemical inhibition of PI3K/AKT cascade by Ly294002 molecule renders psoriatic keratinocytes more susceptible to pro-apoptotic stimuli, such as pro-inflammatory Th1/17-released cytokines (53).…”

Section: Dual Effects Of Pi3k Pathways In Inflammatory and Hyperproliferative Skin Diseasesmentioning

confidence: 99%

Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

2021

Self Cite

View full text Add to dashboard Cite

PhosphoInositide-3 Kinase (PI3K) represents a family of different classes of kinases which control multiple biological processes in mammalian cells, such as cell growth, proliferation, and survival. Class IA PI3Ks, the main regulators of proliferative signals, consists of a catalytic subunit (α, β, δ) that binds p85 regulatory subunit and mediates activation of AKT and mammalian Target Of Rapamycin (mTOR) pathways and regulation of downstream effectors. Dysregulation of PI3K/AKT/mTOR pathway in skin contributes to several pathological conditions characterized by uncontrolled proliferation, including skin cancers, psoriasis, and atopic dermatitis (AD). Among cutaneous cancers, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) display PI3K/AKT/mTOR signaling hyperactivation, implicated in hyperproliferation, and tumorigenesis, as well as in resistance to apoptosis. Upregulation of mTOR signaling proteins has also been reported in psoriasis, in association with enhanced proliferation, defective keratinocyte differentiation, senescence-like growth arrest, and resistance to apoptosis, accounting for major parts of the overall disease phenotypes. On the contrary, PI3K/AKT/mTOR role in AD is less characterized, even though recent evidence demonstrates the relevant function for mTOR pathway in the regulation of epidermal barrier formation and stratification. In this review, we provide the most recent updates on the role and function of PI3K/AKT/mTOR molecular axis in the pathogenesis of different hyperproliferative skin disorders, and highlights on the current status of preclinical and clinical studies on PI3K-targeted therapies.

show abstract

“…The mechanism may be related to cell senescence with SASP, which involves the secretion of soluble factors, such as IGFBPs that perform extracellular and intracellular functions in an IGF-dependent or -independent manner. Interestingly, while extracellular IGFBP2 counter-regulates IGF-induced cell hyperproliferation, apoptosis is inhibited by intracellular IGFBP2 via its interaction with p21 to protect itself from ubiquitin-dependent degradation ( Mercurio et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Aging-Related Genes in Idiopathic Pulmonary Fibrosis

2022

Front. Genet.

View full text Add to dashboard Cite

Aging plays a significant role in the occurrence and development of idiopathic pulmonary fibrosis (IPF). In this study, we aimed to identify and verify potential aging-associated genes involved in IPF using bioinformatic analysis. The mRNA expression profile dataset GSE150910 available in the Gene Expression Omnibus (GEO) database and R software were used to identify the differentially expressed aging-related genes involved in IPF. Hub gene expression was validated by other GEO datasets. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on differentially expressed aging-related genes. Subsequently, aging-related genes were further screened using three techniques (least absolute shrinkage and selection operator (LASSO) regression, support vector machine, and random forest), and the receiver operating characteristic curves were plotted based on screening results. Finally, real-time quantitative polymerase chain reaction (qRT-PCR) was performed to verify the RNA expression of the six differentially expressed aging-related genes using the blood samples of patients with IPF and healthy individuals. Sixteen differentially expressed aging-related genes were detected, of which the expression of 12 were upregulated and four were downregulated. GO and KEGG enrichment analyses indicated the presence of several enriched terms related to senescence and apoptotic mitochondrial changes. Further screening by LASSO regression, support vector machine, and random forest identified six genes (IGF1, RET, IGFBP2, CDKN2A, JUN, and TFAP2A) that could serve as potential diagnostic biomarkers for IPF. Furthermore, qRT-PCR analysis indicated that among the above-mentioned six aging-related genes, only the expression levels of IGF1, RET, and IGFBP2 in patients with IPF and healthy individuals were consistent with the results of bioinformatic analysis. In conclusion, bioinformatics analysis identified 16 potential aging-related genes associated with IPF, and clinical sample validation suggested that among these, IGF1, RET, and IGFBP2 might play a role in the incidence and prognosis of IPF. Our findings may help understand the pathogenesis of IPF.

show abstract

Intracellular Insulin-like growth factor binding protein 2 (IGFBP2) contributes to the senescence of keratinocytes in psoriasis by stabilizing cytoplasmic p21

Cited by 25 publications

References 60 publications

Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging

Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging

Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders

Identification and Validation of Aging-Related Genes in Idiopathic Pulmonary Fibrosis

Contact Info

Product

Resources

About