Sensitivity of the kinase activity of human vaccinia-related kinase proteins to toxic metals

Barcia-Sanjurjo, Iria; Vázquez-Cedeira, Marta; Barcia, Ramiro; Lazo, Pedro A.

doi:10.1007/s00775-013-0992-6

Cited by 18 publications

(15 citation statements)

References 59 publications

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“…These structural differences led to the proposal that VRK proteins are likely have a low sensitivity to most inhibitors, and thus specific inhibitors will have little cross reactivity with other kinases, thus VRK proteins have a low promiscuity index [40, 41]. Their low sensitivity to currently used kinase inhibitors supports this idea [40, 42, 43]. Development of specific inhibitors for VRK1 is highly likely and they might be very useful for cancer treatment in two ways.…”

Section: Resultsmentioning

confidence: 99%

Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

et al. 2014

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Vaccinia-related kinase 1 (VRK1) belongs to a group of sixteen kinases associated to a poorer prognosis in human breast carcinomas, particularly in estrogen receptor positive cases based on gene expression arrays. In this work we have studied the potential molecular mechanism by which the VRK1 protein can contribute to a poorer prognosis in this disease. For this aim it was first analyzed by immunohistochemistry the VRK1 protein level in normal breast and in one hundred and thirty six cases of human breast cancer. The effect of VRK1 to protect against DNA damage was determined by studying the effect of its knockdown on the formation of DNA repair foci assembled on 53BP1 in response to treatment with ionizing radiation or doxorubicin in two breast cancer cell lines. VRK1 protein was detected in normal breast and in breast carcinomas at high levels in ER and PR positive tumors. VRK1 protein level was significantly lower in ERBB2 positive cases. Next, to identify a mechanism that can link VRK1 to poorer prognosis, VRK1 was knocked-down in two breast cancer cell lines that were treated with ionizing radiation or doxorubicin, both inducing DNA damage. Loss of VRK1 resulted in reduced formation of DNA-damage repair foci complexes assembled on the 53BP1 scaffold protein, and this effect was independent of damaging agent or cell type. This observation is consistent with detection of high VRK1 protein levels in ER and PR positive breast cancers. We conclude that VRK1 can contribute to make these tumors more resistant to DNA damage-based therapies, such as ionizing radiation or doxorubicin, which is consistent with its association to a poor prognosis in ER positive breast cancer. VRK1 is potential target kinase for development of new specific inhibitors which can facilitate sensitization to other treatments in combination therapies; or alternatively be used as a new cancer drugs.

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Section: Resultsmentioning

confidence: 99%

Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

et al. 2014

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“…MT3 silenced in untransformed UROtsa cells, was expressed after cadmium transformation and this was mediated by metal transcription factor 1 (MTF1) binding to a metallothionein (MT) metal responsive element (MRE); of special interest was that MTF1 binding was significantly increased in the presence of a HDAC inhibitor, suggesting that histone modification in cadmium-transformed cells is necessary for maximal transcription factor binding and gene activation (Somji et al, 2011). In addition to altering methylation of histone H3 lysine residues, cadmium was shown in vitro to decrease H3 auto-phosphorylation by inhibition of the human vaccinia-related kinase VRK1/2 (Barcia-Sanjurjo et al, 2013), demonstrating that cadmium may block histone modifications through inhibition of histone modifying enzymes.…”

Section: Metals and Epigenetic Alterationsmentioning

confidence: 99%

Incorporating epigenetic data into the risk assessment process for the toxic metals arsenic, cadmium, chromium, lead, and mercury: strategies and challenges

2014

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Exposure to toxic metals poses a serious human health hazard based on ubiquitous environmental presence, the extent of exposure, and the toxicity and disease states associated with exposure. This global health issue warrants accurate and reliable models derived from the risk assessment process to predict disease risk in populations. There has been considerable interest recently in the impact of environmental toxicants such as toxic metals on the epigenome. Epigenetic modifications are alterations to an individual's genome without a change in the DNA sequence, and include, but are not limited to, three commonly studied alterations: DNA methylation, histone modification, and non-coding RNA expression. Given the role of epigenetic alterations in regulating gene and thus protein expression, there is the potential for the integration of toxic metal-induced epigenetic alterations as informative factors in the risk assessment process. In the present review, epigenetic alterations induced by five high priority toxic metals/metalloids are prioritized for analysis and their possible inclusion into the risk assessment process is discussed.

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“…Endogenous VRK1 protein was immunoprecipitated with monoclonal antibody 1F6 as previously reported [44,45] and the immunoprecipitate was used for an in vitro kinase assay [46] showing either endogenous VRK1 autophosphorylation or phosphorylation of GST-p53 (1-85) used as substrate [7,[46][47][48]. The kinase assay was performed at 30°C for 30 min as previously described [47,48].…”

Section: In Vitro Kinase Assaymentioning

confidence: 99%

“…The kinase assay was performed at 30°C for 30 min as previously described [47,48]. Samples were fractionated by SDS-PAGE and radioactivity was detected by exposure to X-ray film in the linear response range.…”

Section: In Vitro Kinase Assaymentioning

confidence: 99%

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

et al. 2014

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a b s t r a c t DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser-Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA-contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1-p53 basal complex is an early-warning system for immediate cellular responses to DNA damage. Structured summary of protein interactions:VRK1 physically interacts with p53 by anti bait coimmunoprecipitation (1, 2, 3, 4) VRK1 physically interacts with p53 by pull down (1,2,3)

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Sensitivity of the kinase activity of human vaccinia-related kinase proteins to toxic metals

Cited by 18 publications

References 59 publications

Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response

Incorporating epigenetic data into the risk assessment process for the toxic metals arsenic, cadmium, chromium, lead, and mercury: strategies and challenges

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

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