scholarly journals Role of Pin1 in the Regulation of p53 Stability and p21 Transactivation, and Cell Cycle Checkpoints in Response to DNA Damage

2002 ◽  
Vol 277 (50) ◽  
pp. 47976-47979 ◽  
Author(s):  
Gerburg M. Wulf ◽  
Yih-Cherng Liou ◽  
Akihide Ryo ◽  
Sam W. Lee ◽  
Kun Ping Lu
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Checkpoints ◽  
P53 Stability

scholarly journals Specific Role of Chk1 Phosphorylations in Cell Survival and Checkpoint Activation

2007 ◽  
Vol 27 (7) ◽  
pp. 2572-2581 ◽  
Author(s):  
Hiroyuki Niida ◽  
Yuko Katsuno ◽  
Birendranath Banerjee ◽  
M. Prakash Hande ◽  
Makoto Nakanishi
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinase ◽  
Cell Survival ◽  
Cell Cycle Checkpoints ◽  
Mitotic Catastrophe ◽  
Wild Type ◽  
Checkpoint Activation ◽  
Multifunctional Protein

ABSTRACT Chk1 is a multifunctional protein kinase that plays essential roles in cell survival and cell cycle checkpoints. Chk1 is phosphorylated at multiple sites by several protein kinases, but the precise effects of these phosphorylations are largely unknown. Using a knockout-knockin system, we examined the abilities of Chk1 mutants to reverse the defects of Chk1-null cells. Wild-type Chk1 could rescue all the defects of Chk1-null cells. Like endogenous Chk1, wild-type Chk1 localized in both the cytoplasm and the nucleus, and its centrosomal association was enhanced by DNA damage. The mutation at S345 resulted in mitotic catastrophe, impaired checkpoints, and loss of the ability to localize in the cytoplasm, but the mutant retained the ability to be released from chromatin upon encountering genotoxic stressors. In contrast, the mutation at S317 resulted in impaired checkpoints and loss of chromatin release upon encountering genotoxic stressors, but its mutant retained the abilities to prevent mitotic catastrophes and to localize in the cytoplasm, suggesting the distinct effects of these phosphorylations. The forced immobilization of S317A/S345A in centrosomes resulted in the prevention of apoptosis in the presence or absence of DNA damage. Thus, two-step phosphorylation of Chk1 at S317 and S345 appeared to be required for proper localization of Chk1 to centrosomes.

scholarly journals Cyclin D1 Promotes Survival and Chemoresistance By Maintaining ATR and CHEK1 Signaling in TP53-Deficient Mantle Cell Lymphoma Cell Lines

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5197-5197
Author(s):  
Suchismita Mohanty ◽  
Thai Tran ◽  
Natalie Sandoval ◽  
Atish Mohanty ◽  
Victoria Bedell ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Cell Cycle Checkpoints ◽  
Mantle Cell ◽  
Induced Apoptosis ◽  
Tp53 Status ◽  
Inducible Gene

Abstract Mantle cell lymphoma (MCL) is a heterogeneous disease, ranging from indolent to aggressive conditions. Prognostic markers that predict aggressive MCL include blastoid cytologic features, high proliferation index (Argatoff et al. 1997), INK4A/ARF locus deletion (Dreyling et al. 1997), TP53 deletion and/or mutations (Greiner et al. 1996), elevated cyclin D1 (CCND1) expression (Rosenwald et al. 2003), and NOTCH1/2 mutations (Kridel et al. 2012, Bea et al. 2013). Among these, TP53 lesions are the most recurrent, suggesting their important role in MCL pathogenesis. In response to DNA damage, TP53 in normal cells activates cell cycle checkpoints to stall DNA replication allowing time for DNA repair or induces apoptosis when damage is severe (Zhou and Elledge. 2000). Tumor cells lacking TP53 function rely on the ATR-CHEK1 signaling for cell cycle checkpoints following DNA damage (Powell et al. 1995). Although both TP53 deficiencies and elevated CCND1 expression levels have been associated with poor survival, possible cooperation of TP53 status and CCND1 expression in aggressive MCL has not been examined. In this study, we hypothesize that CCND1 overexpression collaborates with TP53 deficiency to promote MCL survival and chemoresistance. We compared the effects of CCND1 knockdown on cell survival and resistance to hydroxyurea (HU) and cytarabine to that of knockdown or pharmacological inhibition of CDK4 in MCL lines differing in TP53 status. Inducible gene knockdown was generated in UPN-1 cells to investigate the role of CCND1 in preventing replication stress and DNA damage and in the maintenance of the ATR and CHEK1 signaling. In addition, knockdown of TP53 in TP53-proficient MCL cells was performed to determine the contribution of TP53 status to tumor response to HU and the requirement of CCND1 in the chemosensitivity of these cells. We demonstrate that the survival of TP53-deficient MCL lines (UPN-1 and JEKO-1) is more dependent on CCND1 than on CDK4, but neither of these proteins is essential in TP53-proficient lines (REC-1 and Z-138). Using inducible gene knockdown in UPN-1 cells, we show that CCND1 depletion-induced apoptosis is caused by endogenous replication stress and DNA damage, which are related to defects in the DNA replication checkpoints ATR and CHEK1. The protective effect of CCND1 in MCL cell lines was also confirmed in vivo tumor model. Silencing of CCND1, but not CDK4, sensitizes TP53-deficient MCL cells to hydroxyurea (HU) or cytarabine, which activates the S-phase checkpoint. In addition, forced expression of CCND1 rescues TP53-deficient cells from HU-induced apoptosis in an ATR-dependent manner. In contrast, neither silencing of CCND1 nor CDK4 increases the sensitivity of TP53-proficient cells to these agents. Finally, knockdown of TP53 sensitizes REC-1 cells (TP53 competent) to combination of HU exposure and CCND1 inhibition, confirming the role of TP53 status and CCND1 expression in the chemosensitivity of MCL cells. In summary, these results uncover a novel role for CCND1 in maintaining the ATR and CHEK1 signaling in TP53-deficient MCL. This role of CCND1 could contribute to its oncogenic potential and chemoresistance in aggressive MCL that lack TP53. Disclosures No relevant conflicts of interest to declare.

Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2

2019 ◽  
Vol 105 (3) ◽  
pp. 839-853
Author(s):  
Aglaia Kyrilli ◽  
David Gacquer ◽  
Vincent Detours ◽  
Anne Lefort ◽  
Frédéric Libert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Iodide Uptake ◽  
Transcriptomic Response ◽  
Uptake Inhibition ◽  
Γ Radiation ◽  
Damage Response

Abstract Background The early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes. Methods Following exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response. Results Overall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure. Conclusions TSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.

scholarly journals The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factors ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Double Knockout ◽  
Protein Levels ◽  
Regulation Of Cell Cycle

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

scholarly journals Trp53 ablation fails to prevent microcephaly in mouse pallium with impaired minor intron splicing

2021 ◽  
Author(s):  
Alisa K. White ◽  
Marybeth Baumgartner ◽  
Madisen F. Lee ◽  
Kyle D. Drake ◽  
Gabriela S. Aquino ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Intron Retention ◽  
Conditional Knockout ◽  
Intron Splicing ◽  
Small Nuclear Rna ◽  
Primary Microcephaly ◽  
Double Knockout ◽  
Nuclear Rna

AbstractMutations in minor spliceosome component RNU4ATAC, a small nuclear RNA (snRNA), are linked to primary microcephaly. We have reported that in the conditional knockout (cKO) mice for Rnu11, another minor spliceosome snRNA, minor intron splicing defect in minor intron-containing genes (MIGs) regulating cell cycle resulted in cell cycle defects, with a concomitant increase in γH2aX+ cells and p53-mediated apoptosis. Trp53 ablation in the Rnu11 cKO mice did not prevent microcephaly. However, RNAseq analysis of the double knockout (dKO) pallium reflected transcriptomic shift towards the control from the Rnu11 cKO. We found elevated minor intron retention and alternative splicing across minor introns in the dKO. Disruption of these MIGs resulted in cell cycle defects that were more severe and detected earlier in the dKO, but with delayed detection of γH2aX+ DNA damage. Thus, p53 might also play a role in causing DNA damage in the developing pallium. In all, our findings further refine our understanding of the role of the minor spliceosome in cortical development and identify MIGs underpinning microcephaly in minor spliceosome-related diseases.

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