Abstract
Original language | English |
---|---|
Pages (from-to) | 16744-16754 |
Number of pages | 11 |
Journal | Oncotarget |
Volume | 8 |
Issue number | 10 |
Publication status | Published - 2017 |
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 › peer-review
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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; 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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 -