p53 modifications: exquisite decorations of the powerful guardian

AbstractThe last 40 years have witnessed how p53 rose from a viral binding protein to a central factor in both stress responses and tumor suppression. The exquisite regulation of p53 functions is of vital importance for cell fate decisions. Among the multiple layers of mechanisms controlling p53 function, posttranslational modifications (PTMs) represent an efficient and precise way. Major p53 PTMs include phosphorylation, ubiquitination, acetylation, and methylation. Meanwhile, other PTMs like sumoylation, neddylation, O-GlcNAcylation, adenosine diphosphate (ADP)-ribosylation, hydroxylation, and β-hydroxybutyrylation are also shown to play various roles in p53 regulation. By independent action or interaction, PTMs affect p53 stability, conformation, localization, and binding partners. Deregulation of the PTM-related pathway is among the major causes of p53-associated developmental disorders or diseases, especially in cancers. This review focuses on the roles of different p53 modification types and shows how these modifications are orchestrated to produce various outcomes by modulating p53 activities or targeted to treat different diseases caused by p53 dysregulation.

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Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration

Life ◽

10.3390/life11020153 ◽

2021 ◽

Vol 11 (2) ◽

pp. 153

Author(s):

Gregory J. Gillispie ◽

Eric Sah ◽

Sudarshan Krishnamurthy ◽

Mohamed Y. Ahmidouch ◽

Bin Zhang ◽

...

Keyword(s):

Stress Response ◽

Neurodegenerative Diseases ◽

Cell Fate ◽

Cellular Senescence ◽

Stress Responses ◽

Cellular Stress ◽

Surrounding Tissue ◽

Brain Cells ◽

Cell Fate Decisions ◽

The Brain

Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain.

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Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2)

10.1101/2021.02.06.428911 ◽

2021 ◽

Author(s):

Shilpita Karmakar ◽

Oscar Ramirez ◽

Kiran V. Paul ◽

Abhishek K. Gupta ◽

Valentina Botti ◽

...

Keyword(s):

Cell Fate ◽

Rna Binding ◽

Asymmetric Cell Division ◽

Elongation Factor ◽

Cell Fate Decisions ◽

Translational Repressor ◽

Binding Partners ◽

Genome Wide ◽

Polysome Profiling ◽

Eukaryotic Elongation Factor

ABSTRACTMusashi 2 (MSI2) is an RNA binding protein (RBP) that regulates asymmetric cell division and cell fate decisions in normal and cancer stem cells. MSI2 appears to repress translation by binding to 3’ untranslated regions (3’UTRs) of mRNA, but the identity of functional targets remains unknown. Here we used iCLIP to identify direct RNA binding partners of MSI2 and integrated these data with polysome profiling to obtain insights into MSI2 function. iCLIP revealed specific MSI2 binding to thousands of target mRNAs largely in 3’UTRs, but translational differences were restricted to a small fraction of these transcripts, indicating that MSI2 regulation is not triggered by simple binding. Instead, the functional targets identified here were bound at higher density and contain more “U/TAG” motifs compared to targets bound non-productively. To further distinguish direct and indirect targets, MSI2 was acutely depleted. Surprisingly, only 50 transcripts were found to undergo translational induction on acute MSI2 loss. Eukaryotic elongation factor 3A (EIF3A) was determined to be an immediate, direct target. We propose that MSI2 down-regulation of EIF3A amplifies these effects on the proteome. Our results also underscore the challenges in defining functional targets of RBP since mere binding does not imply a discernible functional interaction.

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Multisite dependency of an E3 ligase controls monoubiquitylation-dependent cell fate decisions

eLife ◽

10.7554/elife.35407 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 6

Author(s):

Achim Werner ◽

Regina Baur ◽

Nia Teerikorpi ◽

Deniz U Kaya ◽

Michael Rape

Keyword(s):

Neural Crest ◽

Cell Fate ◽

Posttranslational Modifications ◽

E3 Ligase ◽

Cell Fate Decisions ◽

Regulatory Circuit ◽

Dependent Cell ◽

Slow Rise ◽

Regulated Gene Expression ◽

Powerful Mechanism

Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is implemented during development is poorly understood. Here, we have identified a regulatory circuit that controls monoubiquitylation-dependent neural crest specification by the E3 ligase CUL3 and its substrate adaptor KBTBD8. We found that CUL3KBTBD8 monoubiquitylates its essential targets only after these have been phosphorylated in multiple motifs by CK2, a kinase whose levels gradually increase during embryogenesis. Its dependency on multisite phosphorylation allows CUL3KBTBD8 to convert the slow rise in embryonic CK2 into decisive recognition of ubiquitylation substrates, which in turn is essential for neural crest specification. We conclude that multisite dependency of an E3 ligase provides a powerful mechanism for switch-like cell fate transitions controlled by monoubiquitylation.

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Cell-to-cell heterogeneity in p38-mediated cross-inhibition of JNK causes stochastic cell death

10.1101/151852 ◽

2017 ◽

Author(s):

Haruko Miura ◽

Yohei Kondo ◽

Michiyuki Matsuda ◽

Kazuhiro Aoki

Keyword(s):

Single Cell ◽

Cell Fate ◽

Stress Responses ◽

Imaging System ◽

Single Cells ◽

High Specificity ◽

Cellular Heterogeneity ◽

Cell Fate Decisions ◽

Specificity And Sensitivity ◽

Cross Inhibition

AbstractThe stress activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK) and p38, are important players in cell fate decisions in response to environmental stress signals. Crosstalk signaling between JNK and p38 is emerging as an important regulatory mechanism in the inflammatory and stress responses. However, it is still unknown how this crosstalk affects signaling dynamics, cell-to-cell variation, and cellular responses at the single-cell level. To address these questions, we established a multiplexed live-cell imaging system based on kinase translocation reporters to simultaneously monitor JNK and p38 activities with high specificity and sensitivity at single-cell resolution. Various stresses, such as anisomycin, osmotic stress, and UV irradiation, and pro-inflammatory cytokines activated JNK and p38 with various dynamics. In all cases, however, p38 suppressed JNK activity in a cross-inhibitory manner. We demonstrate that p38 antagonizes JNK through both transcriptional and post-translational mechanisms. This cross-inhibition of JNK appears to generate cellular heterogeneity in JNK activity after stress exposure. Our data indicate that this heterogeneity in JNK activity plays a role in fractional killing in response to UV stress. Our highly sensitive multiplexed imaging system enables detailed investigation into the p38-JNK interplay in single cells.One Sentence SummaryCross-inhibition by p38 generates cell-to-cell variability in JNK activity.

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Identification and Characterization of LRR-RLK Family Genes in Potato Reveal Their Involvement in Peptide Signaling of Cell Fate Decisions and Biotic/Abiotic Stress Responses

Cells ◽

10.3390/cells7090120 ◽

2018 ◽

Vol 7 (9) ◽

pp. 120 ◽

Cited By ~ 6

Author(s):

Xiaoxu Li ◽

Ahmad Salman ◽

Cun Guo ◽

Jing Yu ◽

Songxiao Cao ◽

...

Keyword(s):

Solanum Tuberosum ◽

Cell Fate ◽

Stress Responses ◽

Feedback Loop ◽

Peptide Recognition ◽

Cell Fate Decisions ◽

Duplication Events ◽

Peptide Signals ◽

Identification And Characterization

Leucine-rich repeat receptor-like kinases (LRR-RLKs) represent the largest subfamily of receptor-like kinases (RLKs) and play important roles in regulating growth, development, and stress responses in plants. In this study, 246 LRR-RLK genes were identified in the potato (Solanum tuberosum) genome, which were further classified into 14 subfamilies. Gene structure analysis revealed that genes within the same subgroup shared similar exon/intron structures. A signature small peptide recognition motif (RxR) was found to be largely conserved within members of subfamily IX, suggesting that these members may recognize peptide signals as ligands. 26 of the 246 StLRR-RLK genes were found to have arisen from tandem or segmental duplication events. Expression profiling revealed that StLRR-RLK genes were differentially expressed in various organs/tissues, and several genes were found to be responsive to different stress treatments. Furthermore, StLRR-RLK117 was found to be able to form homodimers and heterodimers with StLRR-RLK042 and StLRR-RLK052. Notably, the overlapping expression region of StLRR-RLK117 with Solanum tuberosum WUSCHEL (StWUS) suggested that the CLV3–CLV1/BAM–WUS feedback loop may be conserved in potato to maintain stem cell homeostasis within the shoot apical meristem.

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