Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 16744-16754 |
| Number of pages | 11 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 10 |
| Publication status | Published - 2017 |
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Keywords
- Cancer stem cells
- DNA-damage response
- HIPK2
- Phosphorylation
- caspase
- doxorubicin
- homeodomain interacting protein kinase 2
- mutant protein
- phosphotransferase
- proline
- protein p21
- protein p53
- serine
- threonine
- carrier protein
- HIPK2 protein, human
- Hipk2 protein, mouse
- protein serine threonine kinase
- antibody specificity
- Article
- autophosphorylation
- cancer inhibition
- cell count
- cell nucleus
- cell viability
- cellular distribution
- cellular stress response
- colorectal cancer
- controlled study
- enzyme activation
- enzyme active site
- enzyme activity
- enzyme analysis
- enzyme localization
- enzyme phosphorylation
- human
- human cell
- mutation
- protein cleavage
- protein expression
- radiation response
- ultraviolet radiation
- animal
- Bone Neoplasms
- drug effects
- enzymology
- genetic transfection
- genetics
- metabolism
- mouse
- osteosarcoma
- phosphorylation
- tumor cell line
- Animals
- Carrier Proteins
- Cell Line, Tumor
- Doxorubicin
- Enzyme Activation
- Humans
- Mice
- Osteosarcoma
- Protein-Serine-Threonine Kinases
- Transfection
- Ultraviolet Rays
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HIPK2-T566 autophosphorylation diversely contributes to UV- and doxorubicin-induced HIPK2 activation. / Verdina, A.; Di Rocco, G.; Virdia, I.; Monteonofrio, L.; Gatti, V.; Policicchio, E.; Bruselles, A.; Tartaglia, M.; Soddu, S.
In: Oncotarget, Vol. 8, No. 10, 2017, p. 16744-16754.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - HIPK2-T566 autophosphorylation diversely contributes to UV- and doxorubicin-induced HIPK2 activation
AU - Verdina, A.
AU - Di Rocco, G.
AU - Virdia, I.
AU - Monteonofrio, L.
AU - Gatti, V.
AU - Policicchio, E.
AU - Bruselles, A.
AU - Tartaglia, M.
AU - Soddu, S.
N1 - Cited By :1 Export Date: 6 April 2018 Correspondence Address: Soddu, S.; Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute - IRCCSItaly; email: silvia.soddu@ifo.gov.it Chemicals/CAS: caspase, 186322-81-6; doxorubicin, 23214-92-8, 25316-40-9; phosphotransferase, 9031-09-8, 9031-44-1; proline, 147-85-3, 7005-20-1; protein p21, 85306-28-1; serine, 56-45-1, 6898-95-9; threonine, 36676-50-3, 72-19-5; carrier protein, 80700-39-6; protein serine threonine kinase; Carrier Proteins; Doxorubicin; HIPK2 protein, human; Hipk2 protein, mouse; Protein-Serine-Threonine Kinases Tradenames: adriamycin References: Calzado, M.A., De La Vega, L., Munoz, E., Schmitz, M.L., From top to bottom: the two faces of HIPK2 for regulation of the hypoxic response (2009) Cell Cycle, 8, pp. 1659-1664; D'Orazi, G., Rinaldo, C., Soddu, S., Updates on HIPK2: a resourceful oncosuppressor for clearing cancer (2012) J Exp Clin Cancer Res, 31, pp. 1-8; Hofmann, T.G., Glas, C., Bitomsky, N., HIPK2: A tumour suppressor that controls DNA damage-induced cell fate and cytokinesis (2013) Bioessays, 35, pp. 55-64; Wook Choi, D., Yong Choi, C., HIPK2 modification code for cell death and survival (2014) Mol Cell Oncol, 1; de la Vega, L., Fröbius, K., Moreno, R., Calzado, M.A., Geng, H., Schmitz, M.L., Control of nuclear HIPK2 localization and function by a SUMO interaction motif (2011) Biochim Biophys Acta, 13, pp. 283-297; Winter, M., Sombroek, D., Dauth, I., Moehlenbrink, J., Scheuermann, K., Crone, J., Hofmann, T.G., Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR (2008) Nat Cell Biol, 10, pp. 812-824; Rinaldo, C., Prodosmo, A., Mancini, F., Iacovelli, S., Sacchi, A., Moretti, F., Soddu, S., MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis (2007) Mol Cell, 25, pp. 739-750; Choi, D.W., Seo, Y.M., Kim, E.A., Sung, K.S., Ahn, J.W., Park, S.J., Lee, S.R., Choi, C.Y., Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by WD40 repeat/SOCS box protein WSB-1 (2008) J Biol Chem, 283, pp. 4682-4689; Sombroek, D.H.T., How cells switch HIPK2 on and off (2009) Cell Death Differ, 16, pp. 187-194; Kim, S.Y., Choi, D.W., Kim, E.A., Choi, C.Y., Stabilization of HIPK2 by escape from proteasomal degradation mediated by the E3 ubiquitin ligase Siah1 (2009) Cancer Lett, 279, pp. 177-184; D'Orazi, G., Cecchinelli, B., Bruno, T., Manni, I., Higashimoto, Y., Saito, S., Gostissa, M., Soddu, S., Homeodomaininteracting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis (2002) Nat Cell Biol, 4, pp. 11-19; Hofmann, T.G., Möller, A., Sirma, H., Zentgraf, H., Taya, Y., Dröge, W., Will, H., Schmitz, M.L., Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2 (2002) Nat Cell Biol, 4, pp. 1-10; Zhang, Q., Yoshimatsu, Y., Hildebrand, J., Frisch, S.M., Goodman, R.H., Cell Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP (2003) Cell, 115, pp. 177-186; Dauth, I., Krüger, J., Hofmann, T.G., Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM (2007) Cancer Res, 67, pp. 2274-2279; Lazzari, C., Prodosmo, A., Siepi, F., Rinaldo, C., Galli, F., Gentileschi, M., Bartolazzi, A., Soddu, S., HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage (2011) Oncogene, 30, pp. 4802-4813; Gresko, E., Roscic, A., Ritterhoff, S., Vichalkovski, A., del Sal, G., Schmitz, M.L., Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2 (2006) EMBO J, 25, pp. 1883-1894; de la Vega, L., Grishina, I., Moreno, R., Krüger, M., Braun, T., Schmitz, M.L., A redox-regulated SUMO/acetylation switch of HIPK2 controls the survival threshold to oxidative stress (2012) Mol Cell, 46, pp. 472-483; Saul, V.V., Schmitz, M.L., Post-translational modifications regulate HIPK2, a driver of proliferative diseases (2013) J Mol Med (Berl), 91, pp. 1051-1058; Saul, V.V., de la Vega, L., Milanovic, M., Krüger, M., Braun, T., Fritz-Wolf, K., Becker, K., Schmitz, M.L., HIPK2 kinase activity depends on cis-autophosphorylation of its activation loop (2013) J Mol Cell Biol, 5, pp. 27-38; Siepi, F., Gatti, V., Camerini, S., Crescenzi, M., Soddu, S., HIPK2 catalytic activity and subcellular localization are regulated by activation-loop Y354 autophosphorylation (2013) Biochim Biophys Acta, 1833, pp. 1443-1453; van der Laden, J., Soppa, U., Becker, W., Effect of tyrosine autophosphorylation on catalytic activity and subcellular localisation of homeodomain-interacting protein kinases (HIPK) (2015) Cell Commun Signal, 13, pp. 1-11; Bitomsky, N., Conrad, E., Moritz, C., Polonio-Vallon, T., Sombroek, D., Schultheiss, K., Glas, C., Hofmann, T.G., Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death (2013) Proc Natl Acad Sci U S A, 110, pp. E4203-E4212; Reuven, N., Adler, J., Porat, Z., Polonio-Vallon, T., Hofmann, T.G., Shaul, Y., The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage (2015) J Biol Chem, 290, pp. 16478-16488; Choi, D.W., Na, W., Kabir, M.H., Yi, E., Kwon, S., Yeom, J., Ahn, J.W., Choi, C.Y., WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation (2013) Mol Cell, 51, pp. 374-385; Lee, S., Shang, Y., Redmond, S.A., Urisman, A., Tang, A.A., Li, K.H., Burlingame, A.L., Huang, E.J., Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis (2016) Neuron, 91, pp. 41-55; Kwon, M.J., Min, S.K., Seo, J., Kim, D.H., Sung, C.O., Lim, M.S., Cho, J., Park, H.R., HIPK2 expression in progression of cutaneous epithelial neoplasm (2015) Int J Dermatol, 54, pp. 347-354; Nardinocchi, L., Puca, R., Givol, D., D'Orazi, G., HIPK2-a therapeutical target to be (re)activated for tumor suppression: role in p53 activation and HIF-1a inhibition (2010) Cell Cycle, 9, pp. 1270-1275; Fan, Y., Wang, N., Chuang, P., John, C., He Role of HIPK2 in kidney fibrosis (2014) Kidney International Supplements, 4, pp. 97-101; Li, X.L., Arai, Y., Harada, H., Shima, Y., Yoshida, H., Rokudai, S., Aikawa, Y., Kitabayashi, I., Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1-and p53-mediated transcription (2007) Oncogene, 26, pp. 7231-7239; De Angelis, M.L., Zeuner, A., Policicchio, E., Russo, G., Bruselles, A., Signore, M., Vitale, S., Amoreo, C.A., Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance (2016) Stem Cells Transl Med, 5, pp. 511-523; Kircher, M., Witten, D.M., Jain, P., O'Roak, B.J., Cooper, G.M., Shendure, J., A general framework for estimating the relative pathogenicity of human genetic variants (2014) Nat Genet, 46, pp. 310-315; Wiggins, A.K., Wei, G., Doxakis, E., Wong, C., Tang, A.A., Zang, K., Luo, E.J., Huang, E.J., Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival (2004) J Cell Biol, 167, pp. 257-267; Zhang, J., Pho, V., Bonasera, S.J., Holtzman, J., Tang, A.T., Hellmuth, J., Tang, S., Huang, E.J., Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons (2007) Nat Neurosci, 10, pp. 77-96; Rinaldo, C., Moncada, A., Gradi, A., Ciuffini, L., D'Eliseo, D., Siepi, F., Prodosmo, A., Soddu, S., HIPK2 controls cytokinesis and prevents tetraploidization by phosphorylating histone H2B at the midbody (2012) Mol Cell, 47, pp. 87-98; Puca, R., Nardinocchi, L., Givol, D., D'Orazi, G., Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells (2010) Oncogene, 29, pp. 4378-4387; Taira, N., Nihira, K., Yamaguchi, T., Miki, Y., Yoshida, K., DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage (2007) Mol Cell, 25, pp. 725-738; Di Rocco, G., Verdina, A., Gatti, V., Virdia, I., Toietta, G., Todaro, M., Stassi, G., Soddu, S., Apoptosis induced by a HIPK2 fulllength-specific siRNA is due to off-target effects rather than prevalence of HIPK2-Δe8 isoform (2016) Oncotarget, 7, pp. 1675-1686; Li, H., Durbin, R., Fast and accurate short read alignment with Burrows-Wheeler transform (2009) Bioinformatics, 25, pp. 1754-1760; McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., DePristo, M.A., The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data (2010) Genome Res, 20, pp. 1297-1303; Cibulskis, K., Lawrence, M.S., Carter, S.L., Sivachenko, A., Jaffe, D., Sougnez, C., Gabriel, S., Getz, G., Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples (2013) Nat Biotechnol, 31, pp. 213-219; DePristo, M.A., Banks, E., Poplin, R., Garimella, K.V., Maguire, J.R., Hartl, C., Philippakis, A.A., Kernytsky, A.M., A framework for variation discovery and genotyping using next-generation DNA sequencing data (2011) Nat Genet, 43, pp. 491-498; Cordeddu, V., Redeker, B., Stellacci, E., Jongejan, A., Fragale, A., Bradley, T.E., Anselmi, M., Carvalho, D.R., Mutations in ZBTB20 cause Primrose syndrome (2014) Nat Genet, 46, pp. 815-817; Niceta, M., Stellacci, E., Gripp, K.W., Zampino, G., Kousi, M., Anselmi, M., Traversa, A., Bruselles, A., Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a Down syndrome-like Facies (2015) Am J Hum Genet, 96, pp. 816-825; Cingolani, P., Platts, A., Wang le, L., Coon, M., Nguyen, T., Wang, L., Land, S.J., Ruden, D.M., A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3 (2012) Fly (Austin), 6, pp. 80-92; Liu, X., Jian, X., Boerwinkle, E., dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations (2013) Hum Mutat, 34, pp. E2393-E2402; Kortüm, F., Caputo, V., Bauer, C.K., Stella, L., Ciolfi, A., Alawi, M., Bocchinfuso, G., Leuzzi, V., Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome (2015) Nat Genet, 47, pp. 661-667; Flex, E., Niceta, M., Cecchetti, S., Thiffault, I., Au, M.G., Capuano, A., Piermarin, E., Haaxma, C.A., Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy (2016) Am J Hum Genet, 99, pp. 1-12; Ricci-Vitiani, L., Lombardi, D.G., Pilozzi, E., Biffoni, M., Todaro, M., Peschle, C., De Maria, R., Identification and expansion of human colon-cancer-initiating cells (2007) Nature, 445, pp. 111-115; Polonio-Vallon, T., Kirkpatrick, J., Krijgsveld, J., Hofmann, T.G., Src kinase modulates the apoptotic p53 pathway by altering HIPK2 localization (2014) Cell Cycle, 13, pp. 115-125; DeNardo, B.D., Holloway, M.P., Ji, Q., Nguyen, K.T., Cheng, Y., Valentine, M.B., Salomon, A., Altura, R.A., Quantitative phosphoproteomic analysis identifies activation of the RET and IGF-1R/IRsignaling pathways in neuroblastoma (2013) PLoS One, 8; Bai, Y., Li, J., Fang, B., Edwards, A., Zhang, G., Bui, M., Eschrich, S., Haura, E.B., Phosphoproteomics identifies driver tyrosine kinases in sarcoma cell lines and tumors (2012) Cancer Res, 72, pp. 2501-2511; Bian, Y., Song, C., Cheng, K., Dong, M., Wang, F., Huang, J., Sun, D., Zou, H., An enzyme assisted RP-RPLC approach for in-depth analysis of human liverphosphoproteome (2014) J Proteomics, 96, pp. 253-262; Wu, X., Tian, L., Li, J., Zhang, Y., Han, V., Li, Y., Xu, X., Zhong, C.Q., Investigation of receptor interacting protein (RIP3)-dependent protein phosphorylationby quantitative phosphoproteomics (2012) Mol Cell Proteomics, 11, pp. 1640-1651; Klammer, M., Kaminski, M., Zedler, A., Oppermann, F., Blencke, S., Marx, S., Müller, S., Schaab, C., Phosphosignature predicts dasatinib response in non-small cell lung cancer (2012) Mol Cell Proteomics, 11, pp. 651-668; Goswami, T., Li, X., Smith, A.M., Luderowski, E.M., Vincent, J.J., Rush, J., Ballif, B.A., Comparative phosphoproteomic analysis of neonatal and adult murine brain (2012) Proteomics, 12, pp. 2185-2189; Yi, T., Zhai, B., Yu, Y., Kiyotsugu, Y., Raschle, T., Etzkorn, M., Seo, H.C., Wagner, G., Quantitative phosphoproteomic analysis reveals system-wide signaling pathwaysdownstream of SDF-1/CXCR4 in breast cancer stem cells (2014) Proc Natl Acad Sci U S A, 111, pp. E2182-E2190; Helou, Y.A., Nguyen, V., Beik, S.P., Salomon, A.R., ERK positive feedback regulates a widespread network of tyrosine phosphorylation sitesacross canonical T cell signaling and actin cytoskeletal proteins in Jurkat T cells (2013) PLoS One, 8; Humphrey, S.J., Yang, G., Yang, P., Fazakerley, D.J., Stöckli, J., Yang, J.Y., James, D.E., Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2 (2013) Cell Metab, 17, pp. 1009-1020; Huttlin, E.L., Jedrychowski, M.P., Elias, J.E., Goswami, T., Rad, R., Beausoleil, S.A., Villén, J., Gygi, S.P., A tissue-specific atlas of mouse protein phosphorylation and expression (2010) Cell, 143, pp. 1174-1189; Stuart, S.A., Houel, S., Lee, T., Wang, N., Old, W.M., Ahn, N.G., A Phosphoproteomic Comparison of B-RAFV600E and MKK1/2 Inhibitors in Melanoma Cells (2015) Mol Cell Proteomics, 14, pp. 1599-1615; Mertins, P., Qiao, J.W., Patel, J., Udeshi, N.D., Clauser, K.R., Mani, D.R., Burgess, M.W., Carr, S.A., Integrated proteomic analysis of post-translational modifications by serial enrichment (2013) Nat Methods, 10, pp. 634-637; Oppermann, F.S., Gnad, F., Olsen, J.V., Hornberger, R., Greff, Z., Kéri, G., Mann, M., Daub, H., Large-scale proteomics analysis of the human kinome (2009) Mol Cell Proteomics, 8, pp. 1751-1764
PY - 2017
Y1 - 2017
N2 - HIPK2 is a Y-regulated S/T kinase involved in various cellular processes, including cell-fate decision during development and DNA damage response. Cis-autophosphorylation in the activation-loop and trans-autophosphorylation at several S/T sites along the protein are required for HIPK2 activation, subcellular localization, and subsequent posttranslational modifications. The specific function of a few of these autophosphorylations has been recently clarified; however, most of the sites found phosphorylated by mass spectrometry in human and/or mouse HIPK2 are still uncharacterized. In the process of studying HIPK2 in human colorectal cancers, we identified a mutation (T566P) in a site we previously found autophosphorylated in mouse Hipk2. Biochemical and functional characterization of this site showed that compared to wild type (wt) HIPK2, HIPK2-T566P maintains nuclear-speckle localization and has only a mild reduction in kinase and growth arresting activities upon overexpression. Next, we assessed cell response following UV-irradiation or treatment with doxorubicin, two well-known HIPK2 activators, by evaluating cell number and viability, p53-Ser46 phosphorylation, p21 induction, and caspase cleavage. Interestingly, cells expressing HIPK2-T566P mutant did not respond to UV-irradiation, while behaved similarly to wt HIPK2 upon doxorubicin-treatment. Evaluation of HIPK2-T566 phosphorylation status by a T566-phospho-specific antibody showed constitutive phosphorylation in unstressed cells, which was maintained after doxorubicin-treatment but inhibited by UV-irradiation. Taken together, these data show that HIPK2-T566 phosphorylation contributes to UV-induced HIPK2 activity but it is dispensable for doxorubicin response.
AB - HIPK2 is a Y-regulated S/T kinase involved in various cellular processes, including cell-fate decision during development and DNA damage response. Cis-autophosphorylation in the activation-loop and trans-autophosphorylation at several S/T sites along the protein are required for HIPK2 activation, subcellular localization, and subsequent posttranslational modifications. The specific function of a few of these autophosphorylations has been recently clarified; however, most of the sites found phosphorylated by mass spectrometry in human and/or mouse HIPK2 are still uncharacterized. In the process of studying HIPK2 in human colorectal cancers, we identified a mutation (T566P) in a site we previously found autophosphorylated in mouse Hipk2. Biochemical and functional characterization of this site showed that compared to wild type (wt) HIPK2, HIPK2-T566P maintains nuclear-speckle localization and has only a mild reduction in kinase and growth arresting activities upon overexpression. Next, we assessed cell response following UV-irradiation or treatment with doxorubicin, two well-known HIPK2 activators, by evaluating cell number and viability, p53-Ser46 phosphorylation, p21 induction, and caspase cleavage. Interestingly, cells expressing HIPK2-T566P mutant did not respond to UV-irradiation, while behaved similarly to wt HIPK2 upon doxorubicin-treatment. Evaluation of HIPK2-T566 phosphorylation status by a T566-phospho-specific antibody showed constitutive phosphorylation in unstressed cells, which was maintained after doxorubicin-treatment but inhibited by UV-irradiation. Taken together, these data show that HIPK2-T566 phosphorylation contributes to UV-induced HIPK2 activity but it is dispensable for doxorubicin response.
KW - Cancer stem cells
KW - DNA-damage response
KW - HIPK2
KW - Phosphorylation
KW - caspase
KW - doxorubicin
KW - homeodomain interacting protein kinase 2
KW - mutant protein
KW - phosphotransferase
KW - proline
KW - protein p21
KW - protein p53
KW - serine
KW - threonine
KW - carrier protein
KW - HIPK2 protein, human
KW - Hipk2 protein, mouse
KW - protein serine threonine kinase
KW - antibody specificity
KW - Article
KW - autophosphorylation
KW - cancer inhibition
KW - cell count
KW - cell nucleus
KW - cell viability
KW - cellular distribution
KW - cellular stress response
KW - colorectal cancer
KW - controlled study
KW - enzyme activation
KW - enzyme active site
KW - enzyme activity
KW - enzyme analysis
KW - enzyme localization
KW - enzyme phosphorylation
KW - human
KW - human cell
KW - mutation
KW - protein cleavage
KW - protein expression
KW - radiation response
KW - ultraviolet radiation
KW - animal
KW - Bone Neoplasms
KW - drug effects
KW - enzymology
KW - genetic transfection
KW - genetics
KW - metabolism
KW - mouse
KW - osteosarcoma
KW - phosphorylation
KW - tumor cell line
KW - Animals
KW - Carrier Proteins
KW - Cell Line, Tumor
KW - Doxorubicin
KW - Enzyme Activation
KW - Humans
KW - Mice
KW - Osteosarcoma
KW - Protein-Serine-Threonine Kinases
KW - Transfection
KW - Ultraviolet Rays
M3 - Article
VL - 8
SP - 16744
EP - 16754
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 10
ER -