Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis

Magni, Martina; Ruscica, Vincenzo; Buscemi, Giacomo; Kim, Ja Eun; Nachimuthu, Benjamin Tamilselvan; Fontanella, Enrico; Delia, Domenico; Zannini, Laura

doi:10.1093/nar/gku1065

Cited by 42 publications

(44 citation statements)

References 42 publications

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“…4 Quantification of protein levels were normalized to loading control and for phosphorylated proteins to total proteins. Proteins were transferred to a PVDF membrane (Protran, Merck Millipore, Darmstadt, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…2 We previously demonstrated that CCAR2, phosphorylated by ATM/ATR and cooperating with the checkpoint kinase Chk2 and the proteasome subunit REG γ , negatively regulates the NAD + -dependent histone deacetylase SIRT1, promoting p53 activation and apoptosis induction in presence of DNA damage. 3, 4 Recently, we also reported that CCAR2 itself modulates the activity of Chk2 towards KRAB-associated protein 1 (KAP1), thus influencing the repair of DNA breaks. 5 …”

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confidence: 99%

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A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation

et al. 2016

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Human CCAR2 has recently emerged as having a pivotal role in the DNA damage response, promoting apoptosis and repair of heterochromatic DNA breaks. However, less is known about the function of CCAR2 in tumor formation and cancer progression. Here, we demonstrate, for the first time, that CCAR2 loss inhibits the proliferation of cancer cells, but preserves the growth of normal cells. Investigating the mechanisms responsible for this differential effect, we found that CCAR2 depletion specifically impairs the activation of AKT pathway in cancer cells, but not in normal cells, by reducing AKT phosphorylation on Ser473. This effect is achieved through the transcriptional upregulation of TRB3 gene and accumulation of TRB3 protein, which then binds to and inhibits the phosphorylation and activation of AKT. The defective activation of AKT finally results in reduced GSK3β phosphorylation, prevention of G1/S transition and inhibition of cancer cell growth. These results establish an important role for CCAR2 in cancer cells proliferation and could shed new light on novel therapeutic strategies against cancer, devoid of detrimental side effects.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation

et al. 2016

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“…Subsequent studies revealed that SIRT1 inhibition by DBC1 results in increased acetylation of p53 that, in turn, mediates p53-dependent apoptosis following DNA damage [16, 17]. Inhibition of SIRT1 by DBC1in the DNA damage response (DDR) depends on ATM-dependent Chk2 activation [18]. This Chk2 activation in turn promotes phosphorylation of the 11S proteasome activator REGγ, which increases REGγ–DBC1 interaction and SIRT1 inhibition [18].…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of SIRT1 by DBC1in the DNA damage response (DDR) depends on ATM-dependent Chk2 activation [18]. This Chk2 activation in turn promotes phosphorylation of the 11S proteasome activator REGγ, which increases REGγ–DBC1 interaction and SIRT1 inhibition [18]. Caspase-dependent processing of DBC1 has also been implicated in its pro-apoptotic activity during tumor necrosis factor alpha (TNFα)-mediated apoptosis [19].…”

Section: Introductionmentioning

confidence: 99%

CARP-1 / CCAR1: A biphasic regulator of cancer cell growth and apoptosis

2015

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Targeted cancer therapy using small molecule inhibitors (SMIs) has been useful in targeting the tumor cells while sparing the normal cells. Despite clinical success of many targeted therapies, their off-target effects and development of resistance are emerging as significant and challenging problems. Thus, there is an urgent need to identify targets to devise new means to treat cancers and their drug-resistant phenotypes. CARP-1/CCAR1 (Cell division cycle and apoptosis regulator 1), a peri-nuclear phospho-protein, plays a dynamic role in regulating cell growth and apoptosis by serving as a co-activator of steroid/thyroid nuclear receptors, β-catenin, Anaphase Promoting Complex/Cyclosome (APC/C) E3 ligase, and tumor suppressor p53. CARP-1/CCAR1 also regulates chemotherapy-dependent apoptosis. CARP-1/CCAR1 functional mimetics (CFMs) are a novel SMIs of CARP-1/CCAR1 interaction with APC/C. CFMs promote apoptosis in a manner independent of p53. CFMs are potent inhibitors of a variety of cancer cells including the drug (Adriamycin or Tamoxifen)-resistant breast cancer cells but not the immortalized breast epithelial cells, while a nano-lipid formulation of the lead compound CFM-4 improves its bioavailability and efficacy in vivo when administered orally. This review focuses on the background and pleiotropic roles of CARP-1/CCAR1 as well as its apoptosis signaling mechanisms in response to chemotherapy in cancer cells.

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“…Additionally, a low-penetrance breast cancer gene, CHEK2 , is also located in proximity to the detected signal. This gene encodes a cell-cycle checkpoint kinase that cooperates with p53, BRCA1 and ATM and regulates cell division in response to DNA damage 153 . Germline mutations and variants of CHEK2 had been implicated in susceptibility to several cancer types 154–158 , including familial pancreatic cancer 41,42,159 .…”

Section: Common Low-risk Susceptibility Locimentioning

confidence: 99%

Inherited pancreatic cancer

Chen¹,

Roberts²,

Klein³

2017

Chin. Clin. Oncol.

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Pancreatic cancers arise through a series of genetic events both inherited and acquired. Inherited genetic changes, both high penetrance and low penetrance, are an important component of pancreatic cancer risk, and may be used to characterize populations who will benefit from early detection. Furthermore, pancreatic cancer patients with inherited mutations may be particularly sensitive to certain targeted agents, providing an opportunity to personalized treatment. Family history of pancreatic cancer is one of the strongest risk factors for the disease, and is associated with an increased risk of caners at other sites, including but not limited to breast, ovarian and colorectal cancer. The goal of this chapter is to discuss the importance of family history of pancreatic cancer, and the known genes that account for a portion of the familial clustering of pancreatic cancer.

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Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis

Cited by 42 publications

References 42 publications

A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation

A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation

CARP-1 / CCAR1: A biphasic regulator of cancer cell growth and apoptosis

Inherited pancreatic cancer

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