Regulation of MDM2 Stability After DNA Damage

Li, Jiaqi; Kurokawa, Manabu

doi:10.1002/jcp.24994

Cited by 43 publications

(35 citation statements)

References 76 publications

(159 reference statements)

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“…ATII cells have been shown to play a central role in the development of lung fibrosis (Lijnen, ; Chao, ; Li & Kurokawa, ). To determine whether deletion of PAI‐1 specifically in ATII cells protects mice from bleomycin‐induced lung fibrosis, 8‐ to 10‐week‐old CKO and wild‐type (PAI‐1 fl/fl ) mice were injected with tamoxifen, challenged with 2 U/kg bleomycin, and euthanized 14 days after bleomycin instillation.…”

Section: Resultsmentioning

confidence: 99%

Serpine 1 induces alveolar type II cell senescence through activating p53‐p21‐Rb pathway in fibrotic lung disease

et al. 2017

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SummarySenescence of alveolar type 2 (ATII) cells, progenitors of the alveolar epithelium, is implicated in the pathogeneses of idiopathic pulmonary fibrosis (IPF), an aging‐related progressive fatal lung disorder with unknown etiology. The mechanism underlying ATII cell senescence in fibrotic lung diseases, however, remains poorly understood. In this study, we report that ATII cells in IPF lungs express higher levels of serpine 1, also known as plasminogen activator inhibitor 1 (PAI‐1), and cell senescence markers p21 and p16, compared to ATII cells in control lungs. Silencing PAI‐1 or inhibition of PAI‐1 activity in cultured rat ATII (L2) cells leads to decreases in p53 serine 18 phosphorylation (p53S18P), p53 and p21 protein expressions; an increase in retinoblastoma protein phosphorylation (ppRb); and a reduction in the sensitivity to bleomycin‐ and doxorubicin‐induced senescence. Silencing p53, on the other hand, abrogates PAI‐1 protein‐stimulated p21 expression and cell senescence. In vivo studies, using ATII cell‐specific PAI‐1 conditional knockout mouse model generated recently in this laboratory, further support the role of PAI‐1 in the activation of p53‐p21‐Rb cell cycle repression pathway, ATII cell senescence, and lung fibrosis induced by bleomycin. This study reveals a novel function of PAI‐1 in regulation of cell cycle and suggests that elevation of PAI‐1 contributes importantly to ATII cell senescence in fibrotic lung diseases.

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Section: Resultsmentioning

confidence: 99%

Serpine 1 induces alveolar type II cell senescence through activating p53‐p21‐Rb pathway in fibrotic lung disease

et al. 2017

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“…In this paper, we have linked the promoter DNA methylation-associated silencing of the lncRNA TP53TG1 to the impaired response of the tumor-suppressor gene p53 to DNA damage that prevents the induction of apoptosis. Thus, the epigenetic inactivation of TP53TG1 can be considered to be another "hit" taken by the p53 network in cancer cells, in addition to the molecular disruption of other key elements of the p53 tumor suppressor and DNA damage response pathway, such as those occurring with the oncogene MDM2 and the tumor suppressor p14 ARF (53,54). Another relevant step toward highlighting a functional role for a lncRNA in cancer cells, in addition to the in vitro and in vivo growth assays, is the characterization of a bona fide mechanism of action of the lncRNA with a probable role in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer

Díaz‐Lagares

Crujeiras

López-Serra

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

144

140

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Long noncoding RNAs (lncRNAs) are important regulators of cellular homeostasis. However, their contribution to the cancer phenotype still needs to be established. Herein, we have identified a p53-induced lncRNA, TP53TG1, that undergoes cancer-specific promoter hypermethylation-associated silencing. In vitro and in vivo assays identify a tumor-suppressor activity for TP53TG1 and a role in the p53 response to DNA damage. Importantly, we show that TP53TG1 binds to the multifaceted DNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. TP53TG1 epigenetic inactivation in cancer cells releases the transcriptional repression of YBX1-targeted growth-promoting genes and creates a chemoresistant tumor. TP53TG1 hypermethylation in primary tumors is shown to be associated with poor outcome. The epigenetic loss of TP53TG1 therefore represents an altered event in an lncRNA that is linked to classical tumoral pathways, such as p53 signaling, but is also connected to regulatory networks of the cancer cell.DNA methylation | long noncoding RNA | epigenetics | cancer

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“…Given that multiple positive and negative regulatory proteins of MDM2 can alter mRNA expression during HDIS, these proteins might contribute to p53 stabilization in HDIS. In addition, there is an increasing number of modulators that affect the MDM2-p53 pathway in a cellular-and context-dependent manner (Fåhraeus and Olivares-Illana, 2014;Li and Kurokawa, 2015). For instance, microRNAs, an emerging group of such regulators, might mediate HSF1 (Hoffman et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Acute HSF1 depletion induces cellular senescence through the MDM2-p53-p21 pathway in human diploid fibroblasts

Oda

Sekimoto

Kurashima

et al. 2018

Journal of Cell Science

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Heat shock transcription factor 1 (HSF1) regulates the expression of a wide array of genes, controls the expression of heat shock proteins (HSPs) as well as cell growth. Although acute depletion of HSF1 induces cellular senescence, the underlying mechanisms are poorly understood. Here, we report that HSF1 depletion-induced senescence (HDIS) of human diploid fibroblasts (HDFs) was independent of HSP-mediated proteostasis but dependent on activation of the p53-p21 pathway, partly because of the increased expression of dehydrogenase/reductase 2 (DHRS2), a putative MDM2 inhibitor. We observed that HDIS occurred without decreased levels of major HSPs or increased proteotoxic stress in HDFs. Additionally, VER155008, an inhibitor of HSP70 family proteins, increased proteotoxicity and suppressed cell growth but failed to induce senescence. Importantly, we found that activation of the p53-p21 pathway resulting from reduced MDM2-dependent p53 degradation was required for HDIS. Furthermore, we provide evidence that increased DHRS2 expression contributes to p53 stabilization and HDIS. Collectively, our observations uncovered a molecular pathway in which HSF1 depletion-induced DHRS2 expression leads to activation of the MDM2-p53-p21 pathway required for HDIS.

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Regulation of MDM2 Stability After DNA Damage

Cited by 43 publications

References 76 publications

Serpine 1 induces alveolar type II cell senescence through activating p53‐p21‐Rb pathway in fibrotic lung disease

Serpine 1 induces alveolar type II cell senescence through activating p53‐p21‐Rb pathway in fibrotic lung disease

Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer

Acute HSF1 depletion induces cellular senescence through the MDM2-p53-p21 pathway in human diploid fibroblasts

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