Molecular mechanisms for the p38-induced cellular senescence in normal human fibroblast

Harada, Gakuro; Qian, Neng; Fujiki, Toshiyuki; Katakura, Yoshinori

doi:10.1093/jb/mvu040

Cited by 19 publications

(13 citation statements)

References 27 publications

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“…It has been reported that p38 signaling pathway was associated with cellular senescence and p38 induced cellular senescence by suppressing the transcription of TERT in normal human fibroblasts. 29,30 Here, we also found that the expression of MMP-3 in CCH fibroblasts was significantly reduced by p38specific inhibitor SB203580 ( Supplementary Fig. S2), indicating the potential role of p38 in CCH.…”

Section: Enhanced Cellular Senescence In Cch Conjunctival Tissuessupporting

confidence: 59%

“…Blocking p38 MAPK signaling in CCH fibroblasts by transfection of siRNA targeting p38, or treatment with the p38-specific inhibitor SB203580, reduced the number of SA-b-Gal-positive cells and increased cell viability, indicating or implying p38 MAPK signaling in the cellular senescence of CCH fibroblasts. Harada et al 30 revealed that p38 induced cellular senescence in normal human fibroblasts by suppressing the transcription of TERT. The p38 MAPK signaling might result in downregulation of TERT in the CCH group.…”

Section: Discussionmentioning

confidence: 99%

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P38-Mediated Cellular Senescence in Conjunctivochalasis Fibroblasts

Xiang

Zhan

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Conjunctivochalasis (CCH) is a common ocular disease and has received extensive attention recently. However, its exact pathogenesis remains largely unknown. Owing to the high morbidity of CCH in older people, this study aimed to investigate whether cellular senescence contributes to CCH progression and the underlying mechanism. METHODS. Loose conjunctival tissues from CCH patients (n ¼ 13) and normal conjunctival tissues from age-matched persons (n ¼ 12) were obtained and the fibroblasts were separately induced and obtained. Cellular senescence, and the expression of senescence-associated genes (p53 and p21) and p38 in CCH conjunctival tissues and normal controls, were determined by senescence-associated b-galactosidase (SA-b-Gal) staining and quantitative (q)RT-PCR, respectively. To explore the effects of p38 on cellular senescence in CCH fibroblasts, small interfering RNA (siRNA) targeting p38 (siP38) and p38-specific inhibitor SB203580 was performed in CCH fibroblasts. Then, cellular senescence, cell viability, reactive oxygen species (ROS) production, and gene expression were detected according to the corresponding methods. RESULTS. CCH conjunctival tissues had significantly more senescent cells, evidenced by more SA-b-Gal-positive cells, and higher expression of senescence-associated genes (p53 and p21) and p38. CCH fibroblasts transfected with siP38 or treated with SB203580 had obviously reduced numbers of senescent cells, decreased ROS production, and increased cell viability, as well as reduced expression of senescence-associated genes. Meanwhile, blocking p38 signaling decreased the expression of p53 and p21. CONCLUSIONS. Therefore, these findings indicate that cellular senescence might be a causative factor for CCH. P38 signaling might play an important role in the progress of cellular senescence in CCH fibroblasts via manipulation of p53/p21 signaling.

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Section: Enhanced Cellular Senescence In Cch Conjunctival Tissuessupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

P38-Mediated Cellular Senescence in Conjunctivochalasis Fibroblasts

Xiang

Zhan

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…p38α is activated by a wide variety of environmental stresses or inflammatory cytokines and is involved in orchestrating cellular response to different signals. Activation of p38α by oxidative stress, in fact by reactive oxygen species (ROS), plays an important role in mediating cell death (Cai et al 2006; Harada et al 2014). For example, ROS-induced p38 activation was shown to inhibit tumorigenesis (Gutiérrez-Uzquiza et al 2012) or to play a role in the pathology of Alzheimer’s disease.…”

Section: Introductionmentioning

confidence: 99%

MAP kinase p38 is a novel target of CacyBP/SIP phosphatase

2017

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Mitogen-activated protein (MAP) kinases are important players in cellular signaling pathways. Recently, it has been shown that CacyBP/SIP serves as a phosphatase for one of the MAP kinases, ERK1/2. Through dephosphorylation of this kinase CacyBP/SIP modulates the transcriptional activity of Elk-1 and the activity of the CREB-BDNF pathway. In this work, using NB2a cell lysate and recombinant proteins, we show that CacyBP/SIP binds and dephosphorylates another member of the MAP kinase family, p38. Analysis of recombinant full-length CacyBP/SIP and its three major domains, N-terminal, middle CS and C-terminal SGS, indicates that the middle CS domain is responsible for p38 dephosphorylation. Moreover, we show that CacyBP/SIP might be implicated in response to oxidative stress. Dephosphorylation of phospho-p38 by CacyBP/SIP in NB2a cells treated with hydrogen peroxide is much more effective than in control ones. In conclusion, involvement of CacyBP/SIP in the regulation of p38 kinase activity, in addition to that of ERK1/2, might point to the function of CacyBP/SIP in pro-survival and pro-apoptotic pathways.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-017-2404-7) contains supplementary material, which is available to authorized users.

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“…Interestingly, HSV-1 has been shown to activate p38 mitogen-activated protein kinase (MAPK) in an ICP27-dependent manner (39,40). This kinase can downregulate telomerase activity by inhibiting hTERT transcription (41). Therefore, it is possible that optimal HSV replication relies on the appropriate timing of telomerase activity.…”

Section: Discussionmentioning

confidence: 99%

The Telomerase Inhibitor MST-312 Interferes with Multiple Steps in the Herpes Simplex Virus Life Cycle

Haberichter

Abbasi

Dedthanou

et al. 2015

J Virol

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The life cycle of herpes simplex virus (HSV) has the potential to be further manipulated to yield novel, more effective therapeutic treatments. Recent research has demonstrated that HSV-1 can increase telomerase activity and that expression of the catalytic component of telomerase, telomerase reverse transcriptase (TERT), alters sensitivity to HSV-dependent apoptosis. Telomerase is a cellular enzyme that synthesizes nucleotide repeats at the ends of chromosomes (telomeres), which prevents shortening of the 3= ends of DNA with each cell division. Once telomeres reach a critical length, cells undergo senescence and apoptosis. Here, we used a cell-permeable, reversible inhibitor of the telomerase enzyme, MST-312, to investigate telomerase activity during HSV infection. Herpes simplex virus (HSV) is well known as the causative agent of cold sores and genital herpes (reviewed in reference 1). When the virus infects tissues other than the oral or genital mucosa, such as ocular and brain tissues, much more serious diseases occur. Initial HSV-1 infections generally occur in toddlers and young children, and over two-thirds of the U.S. population is infected by adulthood (2). Primary infections may be asymptomatic or lead to the formation of characteristic blistering lesions (e.g., on or around the oral mucosa). The host immune system is usually able to clear the virus from infected epithelial tissues. However, HSV-1 establishes a latent infection in neuronal ganglia servicing the site of initial infection and persists there for the lifetime of the infected individual. HSV-1 may then reactivate from its latent state, which leads to recurrent viral replication in the epithelium and the formation of new lesions. Although currently available antiviral agents that act against HSV polymerase (Pol) can limit lytic replication in epithelial tissues, they are unable to eliminate latent HSV infections. Improvement of treatment for HSV disease relies heavily on a better understanding of cellular factors controlling HSV-1 replication in general.One such cellular factor is telomerase. Increased telomerase activity has been detected in cells infected with a variety of herpesviruses (3-11). There is evidence that HSV can mediate elevated telomerase activity during infection. Telomerase activity was found to be between 4 and 8 times greater in cells infected with a replication-defective mutant of HSV than in uninfected counterparts (3). This increase in activity was accompanied by enhanced telomerase reverse transcriptase (TERT) promoter activity.Previously, we determined that the levels of TERT could determine the sensitivity to HSV-dependent apoptosis (HDAP). Specifically, when tumor suppressor pathways were restored in HeLa cells, expression of TERT sensitized the cells to HDAP (12). This finding suggested that telomerase activation was sufficient to confer sensitivity to HDAP in HeLa cells. The initial goal of this study was to determine whether telomerase was necessary for HDAP. To do this, we utilized a small-molecule in...

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Molecular mechanisms for the p38-induced cellular senescence in normal human fibroblast

Cited by 19 publications

References 27 publications

P38-Mediated Cellular Senescence in Conjunctivochalasis Fibroblasts

P38-Mediated Cellular Senescence in Conjunctivochalasis Fibroblasts

MAP kinase p38 is a novel target of CacyBP/SIP phosphatase

The Telomerase Inhibitor MST-312 Interferes with Multiple Steps in the Herpes Simplex Virus Life Cycle

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