Localization of Adenylate Kinase 4 in Mouse Tissues

Miyoshi, Keiko; Akazawa, Yuki; Horiguchi, Taigo; Noma, Takafumi

doi:10.1267/ahc.08012

Cited by 19 publications

(16 citation statements)

References 28 publications

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“…AK4 (adenylate kinase 4) was responsible for cell proliferation, differentiation and cytoskeleton formation[ 34 ]. AK4 catalyzed the reversible transfer of adenosine triphosphate (ATP) or guanosine triphosphate (GTP) to adenosine monophosphate (AMP), and it played a key role in high-energy phosphoryl transfer and consumption of ATP and GTP[ 35 ]. AK4 was also an essential enzyme in energy metabolism in the cytosol, mitochondria and nucleus.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

et al. 2015

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ObjectiveTo search for biomarkers to differentiate primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD).MethodsWe isolated glomeruli from kidney biopsies of 6 patients with adult-onset steroid sensitiveFSGS and 5 patients with MCD, and compared the profiles of glomerular transcriptomes between the two groups of patients using microarray analysis.ResultsAnalysis of differential expressed genes (DEGs) revealed that up-regulated DEGs in FSGS patients compared with MCD patients were primarily involved in spermatogenesis, gamete generation, regulation of muscle contraction, response to unfolded protein, cell proliferation and skeletal system development. The down-regulated DEGs were primarily related to metabolic process, intracellular transport, oxidation/reduction andestablishment of intracellular localization. We validated the expression of the top 6 up-regulated and top 6 down-regulated DEGs using real-time PCR. Membrane metallo-endopeptidase (MME) is a down-regulated gene that was previously identified as a key gene for kidney development. Immunostaining confirmed that the protein expression of MME decreased significantly in FSGS kidneys compared with MCD kidneys.ConclusionsThis report was the first study to examine transcriptomes in Chinese patients with various glomerular diseases. Expressions of MME both in RNA and protein level decreased significantly in glomeruli of FSGS kidneys compared with MCD kidneys. Our data suggested that MME might play a role in the normal physiological function of podocytes and a decrease in MME expression might be related to podocyte injury. We also identified genes and pathways specific for FSGS versus MCD, and our data could help identify potential new biomarkers for the differential diagnosis between these two diseases.

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Section: Discussionmentioning

confidence: 99%

Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

et al. 2015

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“…Additionally, AK4 contains an N-terminal mitochondrial import sequence which mediates localization to the mitochondrial matrix ( 14 ). AK4 is widely expressed in multiple types of tissues such as kidney, heart and liver ( 15 ). AK4 was also reported to participate in protection from oxidative stress ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of AK4 as a novel therapeutic target for serous ovarian cancer

et al. 2020

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The present study aimed to assess the expression level of adenylate kinase 4 (AK4) in human serous ovarian cancer (SOC) tissues and investigate the possible involvement of AK4 in SOC progression. Bioinformatics analysis based on The Cancer Genome Atlas (TCGA) database and immunohistochemical (IHC) assays were performed to assess the expression level of AK4 in human SOC tissues. Clinical pathological features of patients with SOC were also evaluated. Colony formation, MTT, wound healing and Transwell assays were conducted to investigate the effects of AK4 on the proliferation, migration, and invasion of SOC cells in vitro . Mouse xenograft and lung metastasis models were developed to evaluate the effects of AK4 on tumor growth and metastasis in vivo . High expression levels of AK4 were identified in human SOC tissues compared with in normal tissues according to TCGA database and the results of IHC assays. A contribution of AK4 to tumor growth and metastasis of SOC cells in vivo was also shown. The present study confirmed the involvement of AK4 in the progression of SOC, and the results indicated that AK4 could serve as a novel therapeutic target for SOC treatment.

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“…AK2 is essential for growth in D. melanogaster [ 2 ] and a genetic AK2 deficiency in human causes reticular dysgenesis and sensorineural deafness [ 3 , 4 ], indicating the important role of AK2 in hematopoietic differentiation as well as development of auditory organ. Until now, we have studied the structure and function of AK isozymes and reported that they play important roles in cellular energy metabolism [ 2 , 5 – 8 ]. We also reported that the therapeutic efficacy of iron chelator, deferoxamine (DFO) for treating hepatocellular cancer [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4

Fujisawa

Terai

Takami

et al. 2016

J Exp Clin Cancer Res

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BackgroundAdenylate kinase is a key enzyme in the high-energy phosphoryl transfer reaction in living cells. An isoform of this enzyme, adenylate kinase 4 (AK4), is localized in the mitochondrial matrix and is believed to be involved in stress, drug resistance, malignant transformation in cancer, and ATP regulation. However, the molecular basis for the AK4 functions remained to be determined.MethodsHeLa cells were transiently transfected with an AK4 small interfering RNA (siRNA), an AK4 short hairpin RNA (shRNA) plasmid, a control shRNA plasmid, an AK4 expression vector, and a control expression vector to examine the effect of the AK4 expression on cell proliferation, sensitivity to anti-cancer drug, metabolome, gene expression, and mitochondrial activity.ResultsAK4 knockdown cells treated with short hairpin RNA increased ATP production and showed greater sensitivity to hypoxia and anti-cancer drug, cis-diamminedichloro-platinum (II) (CDDP). Subcutaneous grafting AK4 knockdown cells into nude mice revealed that the grafted cells exhibited both slower proliferation and reduced the tumor sizes in response to CDDP. AK4 knockdown cell showed a increased oxygen consumption rate with FCCP treatment, while AK4 overexpression lowered it. Metabolome analysis showed the increased levels of the tricarboxylic acid cycle intermediates, fumarate and malate in AK4 knockdown cells, while AK4 overexpression lowered them. Electron microscopy detected the increased mitochondrial numbers in AK4 knockdown cells. Microarray analysis detected the increased gene expression of two key enzymes in TCA cycle, succinate dehydrogenase A (SDHA) and oxoglutarate dehydrogenease L (OGDHL), which are components of SDH complex and OGDH complex, supporting the metabolomic results.ConclusionsWe found that AK4 was involved in hypoxia tolerance, resistance to anti-tumor drug, and the regulation of mitochondrial activity. These findings provide a new potential target for efficient anticancer therapies by controlling AK4 expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0322-2) contains supplementary material, which is available to authorized users.

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Localization of Adenylate Kinase 4 in Mouse Tissues

Cited by 19 publications

References 28 publications

Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

Identification of AK4 as a novel therapeutic target for serous ovarian cancer

Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4

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