Myc Is Required for Activation of the ATM-Dependent Checkpoints in Response to DNA Damage

Guerra, Lina; Albihn, Ami; Tronnersjö, Susanna; Yan, Qinzi; Guidi, Riccardo; Stenerlöw, Bo; Sterzenbach, Torsten; Josenhans, Christine; Fox, James G.; Schauer, David B.; Thelestam, Mónica; Larsson, Lars‐Gunnar; Henriksson, Marie Arsenian; Frisan, Teresa

doi:10.1371/journal.pone.0008924

Cited by 62 publications

(59 citation statements)

References 45 publications

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“…For example, c-myc is an established oncogene in various types of cancer 35,36 however, overexpression of c-myc surprisingly sensitizes cells to apoptosis. [37][38][39] E2F1 is another transcription factor that governs cell cycle progression and also regulates apoptosis under conditions of genotoxic stress. 40 PELP1 overexpressing human breast cancer cells undergo significantly more apoptosis when treated with 9-cis-RA.…”

Section: Resultsmentioning

confidence: 99%

Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

et al. 2014

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, glutamic acid-and leucine-rich protein-1 (PELP1) is a scaffolding oncogenic protein that functions as a coregulator for a number of nuclear receptors. p53 is an important transcription factor and tumor suppressor that has a critical role in DNA damage response (DDR) including cell cycle arrest, repair or apoptosis. In this study, we found an unexpected role for PELP1 in modulating p53-mediated DDR. PELP1 is phosphorylated at Serine1033 by various DDR kinases like ataxia-telangiectasia mutated, ataxia telangiectasia and Rad3-related or DNAPKc and this phosphorylation of PELP1 is important for p53 coactivation functions. PELP1-depleted p53 (wild-type) breast cancer cells were less sensitive to various genotoxic agents including etoposide, camptothecin or c-radiation. PELP1 interacts with p53, functions as p53-coactivator and is required for optimal activation of p53 target genes under genomic stress. Overall, these studies established a new role of PELP1 in DDRs and these findings will have future implications in our understanding of PELP1's role in cancer progression. Cell Death and Differentiation (2014) 21, 1409-1418; doi:10.1038/cdd.2014.55; published online 2 May 2014 p53 is considered as the guardian of genomic integrity and has an important role in initiating cellular response to various genomic stresses such as cell cycle arrest, senescence, DNA repair and apoptosis.1,2 Loss of p53 or mutations in p53 is observed in 450% of the cases of all cancers.3-5 Stabilization of p53 upon genomic stress and activation of its transcription functions are vital for its central role in the DNA damage/ genomic stress response and in its tumor-suppressive functions.6,7 Upon genomic stress, p53 is stabilized and activated because of a decreased interaction with its E3-ligase MDM2.8 Activated p53 then upregulates expression of target genes, such as p21/WAF1, GADD45, PUMA and NOXA, all of which are important in the cellular decisions for cell cycle arrest or apoptosis. Post-translational modifications of p53, including phosphorylation, acetylation, ubiquitinylation and methylation, 10-12 and interactions with several cofactors 13,14 have a critical role in the p53-mediated transcriptional response to the DNA damage response (DDR). Proline-, glutamic acid-and leucine-rich protein-1 (PELP1), a large multi-domain protein, modulates a number of biological processes and several pathways including estrogen signaling, and cancer progression. 17 It promotes cell proliferation by enhancing G1 to S phase progression via its interactions with the pRb/E2F pathway.25 PELP1 localizes to the nucleolus and has an important role in ribosomal biogenesis.26 PELP1 signaling is also implicated in apoptosis and differentiation, and PELP1 functions as a coactivator of RXR homodimers and RXR-PPAR heterodimers.27 Although PELP1's role in both cell proliferation and differentiation is evident, it is not known how PELP1 would affect p53-mediated DDR functions and whether PELP1 status would affect sensitivity to various genomic stresses.In this study,...

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Section: Resultsmentioning

confidence: 99%

Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

et al. 2014

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“…3). In addition, upon exposure to IR, c-Myc plays a crucial role in the activation of ATM checkpoints [63]. Another explanation is totally contrary to the first, namely, that the proliferative role of Wnt signaling is temporally inhibited in response to IR by three possible manners.…”

Section: Dna Damage Checkpoint Responsesmentioning

confidence: 97%

The Role of Canonical Wnt Signaling in Regulating Radioresistance

Zhao

Tao

et al. 2018

Cell Physiol Biochem

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Radioresistance is a major obstacle in radiotherapy for cancer, and strategies are needed to overcome this problem. Currently, radiotherapy combined with targeted therapy such as inhibitors of phosphoinosotide 3-kinase/Akt and epidermal growth factor receptor signaling have become the focus of studies on radiosensitization. Apart from these two signaling pathways, which promote radioresistance, deregulation of Wnt signaling is also associated with the radioresistance of multiple cancers. Wnts, as important messengers in the tumor microenvironment, are involved in cancer progression mainly via canonical Wnt signaling. Their role in promoting DNA damage repair and inhibiting apoptosis facilitates cancer resistance to radiation. Thus, it seems reasonable to target Wnt signaling as a method for overcoming radioresistance. Many small-molecule inhibitors that target the Wnt signaling pathway have been identified and shown to promote radiosensitization. Therefore, a Wnt signaling inhibitor may help to overcome radioresistance in cancer therapy.

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“…We have previously reported that AAV2 infection upregulated expression of both the dimer-and monomer forms of c-Myc in multiple breast cancer lines tested, 16 which suggested that AAV2-regulated expression and/or stabilization of c-Myc could serve to amplify proliferation signals which allow the breast cancer cells to bypass cell cycle checkpoint controls in the presence of damaged cellular DNA. 16 On the other hand, c-Myc is also a protein which limits growth by sensitizing cells to apoptosis, 43 and which has the added potential to regulate DNA damage response upon imposition of genotoxic stress 44 mediated via the inherent endonuclease activity of AAV2 Rep78 and Rep68 proteins. 45 We have previously proposed that in the breast cancer cells, AAV2 regulation of c-Myc activation could potentially mediate simultaneous growth stimulatory (G 1 /S, S, and G 2 phase targeting), and growth inhibitory (apoptosis associated DNA damage) signals which could represent a central unifying mechanism of AAV2-induced cell death in multiple breast cancer types.…”

Section: Aav2-mediated Manipulation Of Cell Cycle Check-points Is Relmentioning

confidence: 99%

Adeno-associated virus type 2 infection of nude mouse human breast cancer xenograft induces necrotic death and inhibits tumor growth

Alam¹,

Bowser

Israr

et al. 2014

Cancer Biology & Therapy

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Myc Is Required for Activation of the ATM-Dependent Checkpoints in Response to DNA Damage

Cited by 62 publications

References 45 publications

Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

The Role of Canonical Wnt Signaling in Regulating Radioresistance

Adeno-associated virus type 2 infection of nude mouse human breast cancer xenograft induces necrotic death and inhibits tumor growth

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