The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression

Torgovnick, Alessandro; Heger, Jan Michel; Liaki, Vasiliki; Isensee, Jörg; Schmitt, Anna; Knittel, Gero; Riabinska, Arina; Beleggia, Filippo; Laurien, Lucie; Leeser, Uschi; Jungreuthmayer, Christian; Siedek, Florian; Vogel, Wenzel; Klümper, Niklas; Nolte, Hendrik; Wittersheim, Maike; Tharun, Lars; Castiglione, Roberta; Krüger, Marcus; Schauß, Astrid; Perner, Sven; Pasparakis, Manolis; Büttner, Reinhard; Persigehl, Thorsten; Hucho, Tim; Herter-Sprie, Grit S.; Schumacher, Björn; Reinhardt, Hans Christian

doi:10.1016/j.celrep.2018.09.079

Cited by 23 publications

(17 citation statements)

References 35 publications

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“…p21 has been linked with DKD previously, but the regulation of p21 and its role in hyperglycemic memory are not known (40)(41)(42)(43). The role of p21 in tubular senescence in DKD is in agreement with previous observations: (i) the level and duration of p21 induction determine the onset of cellular growth arrest, (ii) p21 expression is sufficient to induce senescence, (iii) p21 expression restricted to tubular cells is sufficient to induce renal fibrosis following acute kidney injury (44)(45)(46), and (iv) p21 induces endoreduplication (47), which may impair renal tubular cell recovery following acute kidney injury (48,49). These and the current data support a model in which prolonged and sustained p21 expression causes tubular senescence and compromises tubular repair capacity in DKD patients (50), even after glycemic control has improved.…”

Section: Discussionsupporting

confidence: 91%

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

Al‐Dabet

Shahzad

Elwakiel

et al. 2021

Preprint

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A major therapeutic obstacle in diabetes mellitus is the metabolic or hyperglycemic memory: the persistence of impaired organ function despite improvement of blood glucose. Therapies reversing the hyperglycemic memory and thus improving already established organ-dysfunction are lacking, but urgently needed considering the increasing prevalence of diabetes mellitus worldwide. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with sustained induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, in several independent human samples and in in vitro models. Tubular p21 expression and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans, suggesting that p21 may be a biomarker indicating persistent (memorized) kidney damage. Glucose-mediated p21 induction and tubular senescence were enhanced in mice with reduced levels of the disease resolving protease activated protein C (aPC). Mechanistically, glucose-induced and sustained tubular p21 expression is linked with demethylation of its promoter and reduced DNMT1 expression. aPC reverses already established p21 expression independent of its anticoagulant function through receptor signaling. Accordingly, new pharmacological approaches specifically mimicking aPC signaling (3K3A-aPC, parmodulin-2) enabled the reversal of glucose-mediated sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence contributes to the hyperglycemic memory but can be therapeutically targeted.

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Section: Discussionsupporting

confidence: 91%

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

Al‐Dabet

Shahzad

Elwakiel

et al. 2021

Preprint

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“…The GO analysis results indicated that the altered m 6 A methylated transcripts were mainly associated with intracellular, binding, and cell part, which were closely related to the adverse effect of ROS, implying that the m 6 A modification might be essential for the oxidative stress response in AKI. In addition, further analysis demonstrated that the parent genes of the top three altered methylated mRNAs (Fosl1, Krt20, and Cdkn1a) participated in regulating apoptotic pathways (Torgovnick et al, 2018;. A study conducted by Shen J et al also found that genes with elevated methylation of m 6 A sites were significantly enriched in the cell death processes, such as apoptotic processes (Shen J. et al, 2020).…”

Section: Discussionmentioning

confidence: 98%

Alteration of N6-Methyladenosine RNA Profiles in Cisplatin-Induced Acute Kidney Injury in Mice

Zhao

et al. 2021

Front. Mol. Biosci.

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Aim: To identify the alterations of N6-methyladenosine (m6A) RNA profiles in cisplatin-induced acute kidney injury (Cis-AKI) in mice.Materials and Methods: The total level of m6A and the expression of methyltransferases and demethylases in the kidneys were measured. The profiles of methylated RNAs were determined by the microarray method. Bioinformatics analysis was performed to predict the functions.Results: Global m6A levels were increased after cisplatin treatment, accompanied by the alterations of Mettl3, Mettl14, Wtap, Fto, and Alkbh5. A total of 618 mRNAs and 98 lncRNAs were significantly differentially methylated in response to cisplatin treatment. Bioinformatics analysis indicated that the methylated mRNAs predominantly acted on the metabolic process.Conclusion: M6A epitranscriptome might be significantly altered in Cis-AKI, which is potentially implicated in the development of nephrotoxicity.

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“…In addition, 4-1BB is an established marker of exhausted CD8 + T cells (72,73). Lastly, the p53 target gene Cdkn1a (p21) is a potent CDK inhibitor involved in p53-mediated cell-cycle arrest (74). Reduced expression of Cdkn1a in CD4 + T cells following PD-1 blockade thus might be in line with restored proliferation potential.…”

Section: Human Abc-dlbcl and Murine Mbc-derived Lymphomas Display An Actionable Pd-l1 Expressionmentioning

confidence: 99%

An Autochthonous Mouse Model ofMyd88- andBCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities

Flümann

Rehkämper

Nieper

et al. 2021

Blood Cancer Discovery

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Based on gene expression profiles, diffuse large B-cell lymphoma (DLBCL) is subdivided into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in MYD88 as well as BCL2 copy-number gains. Here, we employ immune phenotyping, RNA sequencing, and wholeexome sequencing to characterize a Myd88-and BCL2-driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased PD-L1 expression compared with GCB-DLBCL. In vivo experiments in our ABC-DLBCL model showed that combined venetoclax and PD-1 blockade significantly increased the overall survival of lymphoma-bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring MYD88 and BCL2 aberrations.SignificAnce: Oncogenic Myd88 and BCL2 cooperate in murine DLBCL lymphomagenesis. The resulting lymphomas display morphologic and transcriptomic features reminiscent of human ABC-DLBCL. Data derived from our Myd88/BCL2-driven autochthonous model demonstrate that combined BCL2 and PD-1 blockade displays substantial preclinical antilymphoma activity, providing preclinical proofof-concept data, which pave the way for clinical translation.

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The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression

Cited by 23 publications

References 35 publications

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

Alteration of N6-Methyladenosine RNA Profiles in Cisplatin-Induced Acute Kidney Injury in Mice

An Autochthonous Mouse Model ofMyd88- andBCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities

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