Uridine Cytidine Kinase Like-1 Enhances Tumor Cell Proliferation and Mediates Protection from Natural Killer-Mediated Killing

Gullickson, Gail; Ambrose, Elise C; Hoover, R G; Kornbluth, Jacki

doi:10.23937/2378-3672/1410018

Cited by 3 publications

(4 citation statements)

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“…Downregulation of UCKL-1 in tumor cells by siRNA slows their proliferation, induces apoptosis and enhances their susceptibility to NK-mediated lysis (Ambrose and Kornbluth, 2009). Conversely, over-expression of UCKL-1 protects tumor cells from NK killing and enhances tumor survival in vitro and in vivo (Gullickson et al, 2016). These data suggest a model where, upon NK-tumor interaction and release of lytic granules, NKLAM enters the tumor cell, ubiquitinates and degrades UCKL-1, thereby promoting cell death.…”

Section: Nklam-mediated Ubiquitination Of Uridine-cytidine Kinase Lik...mentioning

confidence: 90%

Natural Killer Lytic-Associated Molecule (NKLAM): An E3 Ubiquitin Ligase With an Integral Role in Innate Immunity

et al. 2020

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Natural Killer Lytic-Associated Molecule (NKLAM), also designated RNF19B, is a unique member of a small family of E3 ubiquitin ligases. This 14-member group of ligases has a characteristic cysteine-rich RING-IBR-RING (RBR) domain that mediates the ubiquitination of multiple substrates. The consequence of substrate ubiquitination varies, depending on the type of ubiquitin linkages formed. The most widely studied effect of ubiquitination of proteins is proteasome-mediated substrate degradation; however, ubiquitination can also alter protein localization and function. Since its discovery in 1999, much has been deciphered about the role of NKLAM in innate immune responses. We have discerned that NKLAM has an integral function in both natural killer (NK) cells and macrophages in vitro and in vivo. NKLAM expression is required for each of these cell types to mediate maximal killing activity and cytokine production. However, much remains to be determined. In this review, we summarize what has been learned about NKLAM expression, structure and function, and discuss new directions for investigation. We hope that this will stimulate interest in further exploration of NKLAM.

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Section: Nklam-mediated Ubiquitination Of Uridine-cytidine Kinase Lik...mentioning

confidence: 90%

Natural Killer Lytic-Associated Molecule (NKLAM): An E3 Ubiquitin Ligase With an Integral Role in Innate Immunity

et al. 2020

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“…Down-regulation of UCKL-1 in K562, a human erythroleukemia cell line, resulted in decreased tumor cell proliferation and increased spontaneous apoptosis and susceptibility to NK cell lysis [ 15 ]. Overexpression of UCKL-1 in vitro provided protection of K562 cells from NK cell lysis [ 16 ]. In vitro and in vivo overexpression of UCKL-1 in RMA-S cells, a mouse lymphoma cell line, also increased their resistance to NK cell lysis [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Overexpression of UCKL-1 in vitro provided protection of K562 cells from NK cell lysis [ 16 ]. In vitro and in vivo overexpression of UCKL-1 in RMA-S cells, a mouse lymphoma cell line, also increased their resistance to NK cell lysis [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of uridine-cytidine kinase like-1 nucleoside kinase activity and its role in tumor growth

Matchett

Ambrose

Kornbluth

2022

Biochemical Journal

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Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively. Only two human UCKs have been identified, UCK1 and UCK2. Previous studies have shown both enzymes phosphorylate uridine and cytidine using ATP as the phosphate donor. No studies have evaluated the kinase potential of UCKL-1. We cloned and purified UCKL-1 and found that it successfully phosphorylated uridine and cytidine using ATP as the phosphate donor. The catalytic efficiency (calculated as kcat/KM) was 1.2 x 104 s-1, M-1 for uridine and 0.7 x 104 s-1, M-1 for cytidine. Previously, our lab determined UCKL-1 is upregulated in tumor cells, providing protection against natural killer (NK) cell killing activity. We utilized small interfering RNA (siRNA) to downregulate UCKL-1 in vitro and in vivo to determine the effect of UCKL-1 on tumor growth and metastasis. The downregulation of UCKL-1 in YAC-1 lymphoma cells in vitro resulted in decreased cell counts and increased apoptotic activity. Downregulation of UCKL-1 in K562 leukemia cells in vivo led to decreased primary tumor growth and less tumor cell dissemination and metastasis. These results identify UCKL-1 as a bona fide pyrimidine kinase with the therapeutic potential to be a target for tumor growth inhibition and for diminishing or preventing metastasis.

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“…Uridine-cytidine kinase 1 like 1 (UCKL-1) (NP_060329.2) [19] was chosen based on its elevated levels and the enhanced activity in damaged tissues, colon tumors [20], hepatocellular carcinomas [21,22], and under B cell transformation upon Epstein -Barr virus infection [23].…”

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confidence: 99%

Differential expression patterns of AIP, UCKL1, and PKN1 genes in breast cancer of different molecular subtypes

et al. 2023

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Summary. Background: Classification of breast cancer (BC) in the molecular subtypes had the enormous impact on the development of the individualized therapy. Nevertheless, there is a need for additional biomarkers that would help to refine molecular subtypes of BC and propose the therapeutic approach for each patient. Aim: To study differential expression patterns of AIP, UCKL1, and PKN1 genes in blood sera and tumor tissue of patients with BC of different molecular subtypes. Materials and Methods: The total extracellular RNA was isolated from serum of 26 BC patients. cDNAs was synthesized and quantitative polymerase chain reaction was performed. Also, immunohistochemical studies of UCKL, AIP and PKN1 were performed on deparaffined tissue sections. The study was supplemented by a bioinformatic analysis of the publicly available databases. Results: AIP and UCKL-1 extracellular mRNA levels were 100–1000-fold increased in blood sera of all BC patients, compared to the healthy donors. The highest levels were detected in the luminal A and HER2 (ERRB2) BC subtypes. The highest levels of PKN1 were detected blood sera of the patients with luminal B and basal subtypes; its expression levels were just 10–100-fold higher in BC samples compared to healthy donors. Conclusions: The UCKL1, AIP, PKN1 genes are overexpressed at the mRNA level in blood sera of BC patients compared to the sera of healthy individuals. Among three genes under study, only for the AIP gene, the pattern of extracellular mRNA expression in sera paralleled to protein expression in BC tissues of each specified molecular subtype.

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Uridine Cytidine Kinase Like-1 Enhances Tumor Cell Proliferation and Mediates Protection from Natural Killer-Mediated Killing

Cited by 3 publications

References 41 publications

Natural Killer Lytic-Associated Molecule (NKLAM): An E3 Ubiquitin Ligase With an Integral Role in Innate Immunity

Natural Killer Lytic-Associated Molecule (NKLAM): An E3 Ubiquitin Ligase With an Integral Role in Innate Immunity

Characterization of uridine-cytidine kinase like-1 nucleoside kinase activity and its role in tumor growth

Differential expression patterns of AIP, UCKL1, and PKN1 genes in breast cancer of different molecular subtypes

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