The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression

Chen, Jiandong

doi:10.1101/cshperspect.a026104

Cited by 895 publications

(698 citation statements)

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“…It has been shown that H 2 O 2 may activate NF-jB phosphorylation via activation of MEKK1/MAPKKK [ IKK pathway or via spleen tyrosine kinase [46]. As a result, NF-jB may up regulate p53, a critical transcription factor involved in apoptosis [47]. Indeed, simultaneous immunohistochemistry detection of both transcription factors and apoptosis in TPGS treated cells, suggest that NF-jB and p53 are linked to cell death signaling.…”

Section: Discussionmentioning

confidence: 97%

Vitamin E synthetic derivate—TPGS—selectively induces apoptosis in jurkat t cells via oxidative stress signaling pathways: implications for acute lymphoblastic leukemia

et al. 2016

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D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a water-soluble derivative of natural vitamin E commonly used as a drug delivery agent. Recently, TPGS alone has been reported to induce cell death in lung, breast and prostate cancer. However, the effect of TPGS on cancer cell viability remains unclear. Thus, this study was aimed to evaluate the cytotoxic effect of TPGS on human periphral blood lymphocytes (PBL) and on T cell acute lymphocytic leukemia (ALL) Jurkat clone E6-1 cells and its possible mechanism of action. PBL and Jurkat cells were treated with TPGS (10, 20, 40, 60, and 80 μM), and morphological changes in the cell nucleus, mitochondrial membrane potential (ΔΨm), and intracellular reactive oxygen species levels were determined by immune-fluorescence microscopy and flow cytometry. Cellular apoptosis markers were also evaluated by immunocytochemistry. In this study, TPGS induced apoptotic cell death in Jurkat cells, but not in PBL, in a dose-response manner with increasing nuclear DNA fragmentation, increasing cell cycle arrest, and decreasing ΔΨm. Additionally, TPGS increased dichlorofluorescein fluorescence intensity, indicative of H2O2 production, in a dose-independent fashion. TPGS increased DJ-1 Cys(106)-sulfonate, as a marker of intracellular stress and induced the activation of NF-κB, p53 and c-Jun transcription factors. Additionally, it increased the expression of apoptotic markers Bcl-2 related pro-apoptotic proteins Bax and PUMAand activated caspase-3. The antioxidant N-acetyl-L-cysteine and known pharmacological inhibitors protected the cells from the TPGS induced effects. In conclusion, TPGS selectively induces apoptosis in Jurkat cells through two independent but complementary H2O2-mediated signaling pathways. Our findings support the use of TPGS as a potential treatment for ALL.

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Section: Discussionmentioning

confidence: 97%

Vitamin E synthetic derivate—TPGS—selectively induces apoptosis in jurkat t cells via oxidative stress signaling pathways: implications for acute lymphoblastic leukemia

et al. 2016

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“…In this regard, we speculate that, in the absence of PAXX and XLF, ionizing radiation treatment leads to high levels of unrepaired genomic DSBs in the G1-arrested cells that would normally be repaired by core C-NHEJ and that such DSBs may overwhelm the G1 DSB checkpoint that would likely be engaged on release (35), resulting in widespread apoptotic death of released cells.…”

Section: Discussionmentioning

confidence: 99%

PAXX and XLF DNA repair factors are functionally redundant in joining DNA breaks in a G1-arrested progenitor B-cell line

Kumar

Frock

2016

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

105

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Classical nonhomologous end joining (C-NHEJ) is a major mammalian DNA double-strand break (DSB) repair pathway. Core C-NHEJ factors, such as XRCC4, are required for joining DSB intermediates of the G1 phase-specific V(D)J recombination reaction in progenitor lymphocytes. Core factors also contribute to joining DSBs in cycling mature B-lineage cells, including DSBs generated during antibody class switch recombination (CSR) and DSBs generated by ionizing radiation. The XRCC4-like-factor (XLF) C-NHEJ protein is dispensable for V(D)J recombination in normal cells, but because of functional redundancy, it is absolutely required for this process in cells deficient for the ataxia telangiectasia-mutated (ATM) DSB response factor. The recently identified paralogue of XRCC4 and XLF (PAXX) factor has homology to these two proteins and variably contributes to ionizing radiation-induced DSB repair in human and chicken cells. We now report that PAXX is dispensable for joining V(D)J recombination DSBs in G1-arrested mouse pro-B-cell lines, dispensable for joining CSR-associated DSBs in a cycling mouse B-cell line, and dispensable for normal ionizing radiation resistance in both G1-arrested and cycling pro-B lines. However, we find that combined deficiency for PAXX and XLF in G1-arrested pro-B lines abrogates DSB joining during V(D)J recombination and sensitizes the cells to ionizing radiation exposure. Thus, PAXX provides core C-NHEJ factor-associated functions in the absence of XLF and vice versa in G1-arrested pro-B-cell lines. Finally, we also find that PAXX deficiency has no impact on V(D)J recombination DSB joining in ATM-deficient pro-B lines. We discuss implications of these findings with respect to potential PAXX and XLF functions in C-NHEJ.T o repair DNA double-strand breaks (DSBs), mammalian cells use two major DSB repair pathways: homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). HR requires a long homologous template for repair and is active in S/G2 cell cycle phase (1). In contrast, C-NHEJ, which directly ligates DSBs with short (1-4 bp) or no homologies, functions throughout interphase, including during the G1 cell cycle phase (2-4). C-NHEJ repairs diverse DSBs, including those arising ectopically by ionizing radiation as well as DSBs generated as intermediates during V(D)J recombination in developing progenitor (pro)-B and -T lymphocytes and Ig heavy chain (IgH) class switch recombination (CSR) in activated mature B lymphocytes (5). The C-NHEJ pathway has a number of characterized members, including "core" C-NHEJ factors that were so-named in part based on their requirement for joining known types of ends via C-NHEJ and their evolutionary conservation (6). Such core factors include the Ku70 and Ku80 proteins, which form the "Ku" end recognition complex, and the XRCC4 and DNA Ligase4 proteins, which form the C-NHEJ ligation complex (5, 6).Exons that encode Ig and T-cell receptor (TCR) variable region exons are assembled from germline V, D, and J gene segments. This V(D)J recombinatio...

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“…Increased expression of cyclin-dependent kinase inhibitors places a brake on the cell cycle while decrease expression induces proliferation (Okamoto et al, 1995; Waldman et al, 1995; Chiarugi and Ruggiero, 1996; Shin et al, 2000; Swellam et al, 2004; Chu et al, 2008). Numerous reports have shown that Tp53 mediates cell cycle arrest and apoptosis through a variety of pathways (Polyak et al, 1997; Fridman and Lowe, 2003; Amaral et al, 2010; Mollereau and Ma, 2014; Chen, 2016). The significant upregulation of Tp53 in Wnt1;1 KO 2 KO embryos, increased apoptosis, and resultant depletion of NC progenitor cells align with these reports.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 1 and 2 are essential for murine neural crest proliferation, pharyngeal arch development, and craniofacial morphogenesis

Milstone

Lawson

Trivedi

2017

Developmental Dynamics

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Background Craniofacial anomalies involve defective pharyngeal arch development and neural crest function. Copy number variation at 1p35, containing histone deacetylase 1 (Hdac1), or 6q21-22, containing Hdac2, are implicated in patients with craniofacial defects, suggesting an important role in guiding neural crest development. However, the roles of Hdac1 and Hdac2 within neural crest cells remain unknown. Results The neural crest and its derivatives express both Hdac1 and Hdac2 during early murine development. Ablation of Hdac1 and Hdac2 within murine neural crest progenitor cells cause severe hemorrhage, atrophic pharyngeal arches, defective head morphogenesis, and complete embryonic lethality. Embryos lacking Hdac1 and Hdac2 in the neural crest exhibit decreased proliferation and increased apoptosis in both the neural tube and the first pharyngeal arch. Mechanistically, loss of Hdac1 and Hdac2 upregulates cyclin-dependent kinase inhibitors Cdkn1a, Cdkn1b, Cdkn1c, Cdkn2b, Cdkn2c, and Tp53 within the first pharyngeal arch. Conclusions Our results show that Hdac1 and Hdac2 function redundantly within the neural crest to regulate proliferation and the development of the pharyngeal arches via repression of cyclin-dependent kinase inhibitors.

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The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression

Cited by 895 publications

References 121 publications

Vitamin E synthetic derivate—TPGS—selectively induces apoptosis in jurkat t cells via oxidative stress signaling pathways: implications for acute lymphoblastic leukemia

Vitamin E synthetic derivate—TPGS—selectively induces apoptosis in jurkat t cells via oxidative stress signaling pathways: implications for acute lymphoblastic leukemia

PAXX and XLF DNA repair factors are functionally redundant in joining DNA breaks in a G1-arrested progenitor B-cell line

Histone deacetylase 1 and 2 are essential for murine neural crest proliferation, pharyngeal arch development, and craniofacial morphogenesis

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