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You searched for subject:(Thymidine kinase 2). Showing records 1 – 3 of 3 total matches.

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University of Southern California

1. Kouhi, Aida. Characterization of human thymidine kinase 2 activity.

Degree: MS, Pharmaceutical Sciences, 2014, University of Southern California

Although radiolabeled TdR has been used in vitro for measurement of rates of DNA synthesis, rapid in vivo catabolism has limited its utility as a radiotracer targeted at measuring cellular proliferation in vivo. In recent years, development of PET radiotracer has focused on thymidine (TdR) analogs for imaging cell proliferation that are resistant to metabolism in vivo. Thymidine kinases are key enzymes in the salvage pathway of TdR synthesis and have been the targets for designing nucleoside analogues for monitoring cellular proliferation. In this study, a human mitochondrial thymidine kinase (hTK2) was expressed in an attempt to characterize in detail its kinetic parameters. The kinetic data from our experiments were significantly different from previously published data, as well as comparative studies. For future studies the effects of the fusion proteins on the activity of the hTK2 has to be further investigated. Nonetheless, the data presented in this thesis lays a methodological platform for the future screening of novel nucleoside analogues that can be used as radiotracers targeted to the measurement of cellular proliferation in tumors. Advisors/Committee Members: Conti, PeterOkamoto, Curtis Toshio (Committee Chair), Mackay, John Andrew (Committee Member).

Subjects/Keywords: thymidine kinase 2

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APA (6th Edition):

Kouhi, A. (2014). Characterization of human thymidine kinase 2 activity. (Masters Thesis). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/447095/rec/1304

Chicago Manual of Style (16th Edition):

Kouhi, Aida. “Characterization of human thymidine kinase 2 activity.” 2014. Masters Thesis, University of Southern California. Accessed April 14, 2021. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/447095/rec/1304.

MLA Handbook (7th Edition):

Kouhi, Aida. “Characterization of human thymidine kinase 2 activity.” 2014. Web. 14 Apr 2021.

Vancouver:

Kouhi A. Characterization of human thymidine kinase 2 activity. [Internet] [Masters thesis]. University of Southern California; 2014. [cited 2021 Apr 14]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/447095/rec/1304.

Council of Science Editors:

Kouhi A. Characterization of human thymidine kinase 2 activity. [Masters Thesis]. University of Southern California; 2014. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/447095/rec/1304


Swedish University of Agricultural Sciences

2. Sun, Ren. Studies of enzymes in mitochondrial DNA precursor synthesis.

Degree: 2013, Swedish University of Agricultural Sciences

As important enzymes in mitochondrial nucleotide salvage pathway, thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) are expressed constitutively in almost all cells. These two enzymes catalyze the initial rate-limiting phosphorylation of pyrimidine and purine deoxynucleosides, respectively, providing DNA precursors for mitochondrial DNA (mtDNA) replication. Inherited genetic defects in TK2 have been associated with infantile myopathic form of mtDNA depletion syndrome (MDS). In study I, two mutations, R225W and a novel T230A, in TK2 are identified as a new genetic cause of adult-onset autosomal recessive progressive external ophthalmoplegia (arPEO) and the kinetic and structural effects of the two mutations on enzyme function have been characterized. Nucleoside analogs are widely used in anti-viral and anti-cancer chemotherapy, but they can cause severe side-effect such as mtDNA depletion. In study II, the potential mechanism underlying pyrimidine nucleoside analogs-associated mitochondrial toxicities was investigated, and showed that thymidine analogs had opposite effects on dThd and dCyd phosphorylation and thus can inhibit dThd salvage, leading to imbalanced dTTP and dCTP pools. It was found that the mechanism is most likely due to that TK2 normally exists in an inactive form with bound dTTP. The redox regulation of TK2 and dGK was studied in study III and IV. The activity of both enzymes was sensitive to the cellular redox status. Under oxidative stress, both TK2 and dGK can be reversibly S-glutathionylated by GSSG. The modification of the conserved Cys189 in TK2 was responsible for a partial inactivation and selective degradation of TK2 in mitochondria, most likely via the AAA⁺ Lon protease. The oxidative effect of nucleoside analogs was also evaluated. Treatment with 3’-azido- 2’,3’-dideoxythymidine (AZT) and 2’,3’-dideoxyinosine (ddI) led to degradation of mitochondrial TK2 and dGK, whereas uridine and guanosine supplementations to AZT respective ddI treatments prevented both proteins from degradation.

Subjects/Keywords: enzymes; thymidine; kinases; mitochondria; dna; Thymidine kinase 2; Deoxyguanosine kinase; Mitochondrial DNA; Progressive external ophthalmoplegia; Nucleoside analogs; AZT (3’-azido-2’,3’- dideoxythymidine); ddI (2’,3’-dideoxyinosine); S-glutathionylation

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APA (6th Edition):

Sun, R. (2013). Studies of enzymes in mitochondrial DNA precursor synthesis. (Doctoral Dissertation). Swedish University of Agricultural Sciences. Retrieved from http://pub.epsilon.slu.se/10780/

Chicago Manual of Style (16th Edition):

Sun, Ren. “Studies of enzymes in mitochondrial DNA precursor synthesis.” 2013. Doctoral Dissertation, Swedish University of Agricultural Sciences. Accessed April 14, 2021. http://pub.epsilon.slu.se/10780/.

MLA Handbook (7th Edition):

Sun, Ren. “Studies of enzymes in mitochondrial DNA precursor synthesis.” 2013. Web. 14 Apr 2021.

Vancouver:

Sun R. Studies of enzymes in mitochondrial DNA precursor synthesis. [Internet] [Doctoral dissertation]. Swedish University of Agricultural Sciences; 2013. [cited 2021 Apr 14]. Available from: http://pub.epsilon.slu.se/10780/.

Council of Science Editors:

Sun R. Studies of enzymes in mitochondrial DNA precursor synthesis. [Doctoral Dissertation]. Swedish University of Agricultural Sciences; 2013. Available from: http://pub.epsilon.slu.se/10780/


University of Western Ontario

3. Di Cresce, Christine. siRNA Targeting of Thymidylate Synthase, Thymidine Kinase 1 and Thymidine Kinase 2 as an Anticancer Therapy: A Combinatorial RNAi Approach.

Degree: 2014, University of Western Ontario

Thymidylate synthase (TS) is the only de novo source of thymidylate (dTMP) for DNA synthesis and repair. Drugs targeting TS protein are a mainstay in cancer treatment but off-target effects and toxicity limit their use. Cytosolic thymidine kinase (TK1) and mitochondrial thymidine kinase (TK2) contribute to an alternative dTMP-producing pathway, by salvaging thymidine from the tumour milieu, and may modulate resistance to TS-targeting drugs. We have previously shown that TS antisense molecules (oligodeoxynucleotides, ODNs, and small interfering siRNA, siRNA) sensitize tumour cells, both in vitro and in vivo, to TS targeting drugs. As both TS and TKs contribute to cellular dTMP, we hypothesized that TKs mediate resistance to the capacity of TS siRNA to sensitize tumour cells to TS-targeting drugs. Downregulation of TKs with siRNA enhanced the capacity of TS siRNA to sensitize tumour cells to traditional TS protein-targeting drugs (5FUdR and pemetrexed). Combined downregulation of these enzymes is an attractive strategy to enhance TS-targeted anticancer therapy. TK2 can phosphorylate both thymidine and deoxycytidine to generate dTMP and dCMP, precursors for dTTP and dCTP, respectively. dCTP negatively regulates deoxycytidine kinase (dCK), another enzyme that phosphorylates deoxycytidine as well as the anticancer drug gemcitabine. Antisense knockdown of TK2 could reduce TK2-produced dCMP, thus decreasing dCTP levels and inhibition of dCK, and lead to increased dCK activity, gemcitabine activation, and anticancer effectiveness. Given the substrate promiscuity of TK2, we hypothesized that: (1) TK2 can mediate human tumour cell resistance to gemcitabine, (2) antisense downregulation of TK2 can overcome that resistance, and (3) TK2 siRNA-induced drug sensitization results in mitochondrial damage. siRNA downregulation of TK2 expression sensitized MCF7 and HeLa cells to gemcitabine, but did not sensitize A549 cells (low TK2 expresser). Treatment with TK2 siRNA and gemcitabine: 1) decreased mitochondrial redox status, 2) decreased mitochondrial DNA (mtDNA:nDNA ratio), and 3) decreased mitochondrial activity. This is the first demonstration of a direct role for TK2 in gemcitabine resistance, or any independent role in cancer drug resistance, and further distinguishes TK2 from other dTMP-producing enzymes.

Subjects/Keywords: small interfering RNA (siRNA); RNA interference (RNAi); combinatorial RNAi; thymidylate synthase (TS); thymidine kinase 1 (TK1); thymidine kinase 2 (TK2); cancer; anticancer drugs; gemcitabine; deoxycytidine kinase (dCK); anticancer therapy; mitochondrial DNA; mitochondrial activity; Biology; Cancer Biology; Molecular Biology; Pharmacology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Di Cresce, C. (2014). siRNA Targeting of Thymidylate Synthase, Thymidine Kinase 1 and Thymidine Kinase 2 as an Anticancer Therapy: A Combinatorial RNAi Approach. (Thesis). University of Western Ontario. Retrieved from https://ir.lib.uwo.ca/etd/2032

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Di Cresce, Christine. “siRNA Targeting of Thymidylate Synthase, Thymidine Kinase 1 and Thymidine Kinase 2 as an Anticancer Therapy: A Combinatorial RNAi Approach.” 2014. Thesis, University of Western Ontario. Accessed April 14, 2021. https://ir.lib.uwo.ca/etd/2032.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Di Cresce, Christine. “siRNA Targeting of Thymidylate Synthase, Thymidine Kinase 1 and Thymidine Kinase 2 as an Anticancer Therapy: A Combinatorial RNAi Approach.” 2014. Web. 14 Apr 2021.

Vancouver:

Di Cresce C. siRNA Targeting of Thymidylate Synthase, Thymidine Kinase 1 and Thymidine Kinase 2 as an Anticancer Therapy: A Combinatorial RNAi Approach. [Internet] [Thesis]. University of Western Ontario; 2014. [cited 2021 Apr 14]. Available from: https://ir.lib.uwo.ca/etd/2032.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Di Cresce C. siRNA Targeting of Thymidylate Synthase, Thymidine Kinase 1 and Thymidine Kinase 2 as an Anticancer Therapy: A Combinatorial RNAi Approach. [Thesis]. University of Western Ontario; 2014. Available from: https://ir.lib.uwo.ca/etd/2032

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

.