Disease relevance of HK2

• HKII is considered to be a promising candidate gene for non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance [1].
• Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host [2].
• HK II mRNA expression was significantly higher in metastatic liver cancers, however, some cases of HCC pretreated with transcatheter arterial embolization (TAE) showed marked HK II mRNA expression [3].
• We examined the targeting properties of the human hHKII promoter in different human non-small cell lung cancer (NSCLC) and other human cancer cell lines using self-inactivating, VSV-G pseudotyped lentiviral vector [4].
• In adenocarcinomas, cancers with lower differentiation showed higher expression of Glut-1 and HK-II than those with higher differentiation [5].

High impact information on HK2

• In the entire study population HKII activity estimated at 0.11 and 11.0 mM glucose was inversely correlated with fasting plasma glucose concentrations (r = -0.45, P = 0.004; r = -0.54, P < 0.0001, respectively) and fasting plasma nonesterified fatty acid concentrations (r = -0.46, P = 0.003; r = -0.37, P = 0.02, respectively) [6].
• Previous studies in rodents have shown that HKII may be the dominant HK in skeletal muscle [6].
• In the present study comprising 29 NIDDM patients and 25 matched controls, we tested the hypothesis that HKII activity and gene expression are impaired in vastus lateralis muscle of NIDDM patients when examined in the fasting state [6].
• HKII contributes with about one-third of total HK activity in a supernatant of human vastus lateralis muscle [6].
• The second isozyme eluted between HKI and HKII of human white blood cells, and it appeared to be unique to the RBC (it was designated HKR) [7].

Chemical compound and disease context of HK2

• In conclusion, the transcriptionally targeted lentivirus vector with hHKII promoter can successfully direct HSV-TK/GCV suicide gene therapy to non-small cell lung cancer and other tumor cell types [4].
• In muscle, hexokinase II (HK2) regulates phosphorylation of glucose to glucose 6-phosphate, which has been reported to be impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM) [8].
• Since defects involving glucose transport and/or its phosphorylation to glucose-6-phosphate are present in muscle of insulin-resistant humans, HKII should be viewed as a candidate gene for inherited insulin resistance and susceptibility to non-insulin-dependent diabetes mellitus (NIDDM) [9].
• Glucose transporter-1 (Glut-1) and hexokinase II (HKII) proteins are highly expressed in many breast carcinomas, but their status while undergoing DOX or 5FU chemotherapy has not been systematically evaluated [10].
• METHODS: We evaluated, in vitro, the messenger RNA (mRNA) and protein levels of Glut-1 and HKII in MCF-7, a breast adenocarcinoma cell line, and (3)H-FDG uptake, both in untreated conditions and during treatment with either DOX or 5FU for 24 h [10].

Biological context of HK2

• In addition, we have identified and characterized a simple tandem repeat DNA polymorphism in HK2 and used this DNA polymorphism to localize this gene within the genetic linkage map of chromosome 2 [11].
• As a first step, we have cloned the human hexokinase II gene (HK2) and mapped it to human chromosome 2, band p13.1, by fluorescence in situ hybridization to metaphase chromosomes [11].
• The HK1 mRNA was expressed in both the nonlactating and lactating mammary gland tissue, but HK2 mRNA was found only during lactation [12].
• This study was conducted to identify the transcription factors that mediate the effect of insulin on HKII gene expression in human muscle [13].
• We have cloned the promoter region of the HKII gene and investigated its regulation in a primary culture of human skeletal muscle cells [13].

Anatomical context of HK2

• HIF-1alpha, VEGF(165), HK II, HK III, and macrophages showed no univariate correlation with (18)FDG [14].
• Insulin upregulates hexokinase II (HKII) expression in skeletal muscle, and this effect is altered in type 2 diabetic patients [13].
• This region contains a sterol regulatory element (SRE) that interacted with the recombinant active form of SRE binding protein-1c (SREBP-1c) in electrophoretic mobility shift assays, and, using chromatin immunoprecipitation assay, we showed that endogenous SREBP-1 interacted directly with the promoter region of the HKII gene in human muscle cells [13].
• Finally, overexpression of the rodent mature form of SREBP-1c (adipocyte determination and differentiation factor-1 [ADD1]-403) was able to reproduce insulin action, whereas a dominant-negative form (ADD1-403R) prevented the effect of insulin on HKII promoter constructs [13].
• To confirm accurate transcriptional targeting of the hHKII promoter, the lack of transgene expression was verified in human primary bronchial epithelial and bronchial fibroblast cells [4].

Associations of HK2 with chemical compounds

• None of these mutations were located close to the glucose- and ATP-binding sites of HKII [1].
• This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II [2].
• As HKII is a candidate gene that could contribute to the manifestation of insulin resistance and NIDDM, we genotyped 1152 Pima Indians, a Native American tribe that has the highest reported prevalence of NIDDM in the world [15].
• Also, the anti-cancer efficacy of HSV-TK/GCV therapy with the hHKII-targeted vector was comparable to that obtained with the control vector that utilized a commonly used constitutive promoter from the human elongation factor 1 alpha (hEF1alpha) gene [4].
• PURPOSE: The aim of this study was to evaluate the relationships among [18F]fluorodeoxyglucose ([18F]-FDG) uptake, Glut-1 and HK-II expressions, and grade of inflammation in resected lung lesions [5].

Regulatory relationships of HK2

• In response to 40 mU insulin, HKII mRNA in lean control subjects was increased 1.48 +/- 0.18-fold (P < 0.05) but failed to increase significantly in the obese (1.12 +/- 0.24) or NIDDM (1.14 +/- 0.18) groups [16].
• HK-II is the most regulated isoform of HK [17].
• Cells expressing HKII did not always express Glut-1 and vice versa [18].
• Influence of connective tissue growth factor antisense oligonucleotide on angiotensin II-induced epithelial mesenchymal transition in HK2 cells [19].
• These results strongly suggest that HK-II is selectively regulated in pulmonary cells by a HIF-1-dependent mechanism [20].

Other interactions of HK2

• Expression of HIF-1 alpha and HK II protein, and microvessel density (MVD) were examined immunohistochemically [3].
• METHODS: A real-time quantitative reverse transcription-polymerase chain reaction was performed to examine the HK II and VEGF mRNA expression [3].
• Twenty-four hours' refeeding with a CHO-rich diet completely reversed the changes in PDK4, HKII and SREBP1c expression in human skeletal muscle but failed to fully restore whole-body insulin sensitivity [21].
• Expression of hexokinase 1 and hexokinase 2 in mammary tissue of nonlactating and lactating rats: evaluation by RT-PCR [12].
• In the malignant neoplasms studied, a significant elevation of HK-II and the appearance of additional anodal bands (HK-IIf and HK-III) have been demonstrated [22].

Analytical, diagnostic and therapeutic context of HK2

• RNA was extracted from mammary tissue dissected from timed pregnant rats (from gestional days 10 to 21) and nursing rat mothers (up to postnatal day 5) for mRNA examination by reverse transcriptase and polymerase chain reaction (RT-PCR) using isozyme specific oligonucleotide primers to the HK1 and HK2 cDNAs [12].
• We describe improved suicide gene therapy against cancer through transcripitional targeting by a strong and selective tumor-specific human hexokinase II promoter (hHKII) [4].
• In human muscle, a single HK2 mRNA transcript with a size of approximately 5500 nucleotides was detected with Northern blot analysis [8].
• PCR products corresponding to individual HKII exons derived from each subject were screened for the presence of nucleotide variation using a sensitive nonradioactive single-strand conformation polymorphism (SSCP) protocol [9].
• We analyzed tumor cell Glut-1 and HKII mRNA expression with real-time polymerase chain reaction and Western blotting, (3)H-FDG uptake per cell, and cell viability with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay [10].

References