Disease relevance of PROK1

• Chemical hypoxia induced by CoCl(2) and desferrioxamine mesylate (100 micro M each) markedly reduced EG-VEGF/PK-1 [1].
• The expression pattern of EG-VEGF, its regulation by oxygen tension, and its complementary localization to that of VEGF suggest that this new factor might also be deregulated in preeclampsia [2].
• On the other hand, EG-VEGF transcript was rarely detected in the endometrial samples from the postmenopausal patients and patients with endometrial carcinoma [3].
• Thus, the level of EG-VEGF/PK1 could be useful for prostate cancer outcome evaluation and as a target for prostate cancer treatment in the future [4].
• Expression of endocrine gland-derived vascular endothelial growth factor in ovarian carcinoma [5].
• Implication of EG-VEGF/Prok-1 signaling in neuroblastoma progression was further shown in a neuroblastoma cell line (SK-N-SH) [6].

High impact information on PROK1

• Expression of human EG-VEGF messenger RNA is restricted to the steroidogenic glands, ovary, testis, adrenal and placenta and is often complementary to the expression of VEGF, suggesting that these molecules function in a coordinated manner [7].
• This molecule, called endocrine-gland-derived vascular endothelial growth factor (EG-VEGF), induced proliferation, migration and fenestration (the formation of membrane discontinuities) in capillary endothelial cells derived from endocrine glands [7].
• EG-VEGF is an example of a class of highly specific mitogens that act to regulate proliferation and differentiation of the vascular endothelium in a tissue-specific manner [7].
• Systemic in vivo exposure to Bv8 or EG-VEGF resulted in significant increases in total leukocyte, neutrophil, and monocyte counts [8].
• Bv8, or EG-VEGF that shares the same receptors, increased numbers of colony-forming units granulocytic and monocytic in cultures of human or mouse hematopoietic stem cells [8].

Chemical compound and disease context of PROK1

• When the EG-VEGF gene-overexpressing colorectal cancer cell line that had been treated with phosphorothioate antisense EG-VEGF oligonucleotides was injected s.c. into mice, angiogenesis and tumor growth were inhibited [9].
• Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four- to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m2 (doxorubicin equivalent), no cardiotoxicity was observed [10].
• The aim of this study was to establish a subcellular fractionation method for B16F10 murine melanoma cells and subsequently to use it to define the intracellular trafficking of N-(2-hydroxyproplylmethacrylamide) (HPMA) copolymer-bound doxorubicin (PK1) [11].

Biological context of PROK1

• Expression of PK1 was elevated in the secretory compared with the proliferative phase of the menstrual cycle (P < 0.05) [12].
• EG-VEGF is mainly localized to the syncytiotrophoblast layer with the highest expression detected between the 8th and 10th wk of gestation [2].
• These findings suggest that EG-VEGF has a direct effect on TCs via its receptor PKR1 and is likely to play an important role in human placentation [2].
• Therefore, while the MIT-like ACTX family appears to adopt the ancestral disulfide-directed beta-hairpin protein fold of MIT1, a motif believed to be shared by other AVIT family peptides, variations in the amino acid sequence and surface charge result in a loss of activity on prokineticin receptors [13].
• Immunochemistry confirmed that EG-VEGF/PK1 protein expression was restricted to hyperplastic and malignant prostate tissues, localized in the glandular epithelial cells, and progressively increased with the prostate cancer Gleason score advancement [4].

Anatomical context of PROK1

• Endocrine gland vascular endothelial growth factor (EG-VEGF) is a novel angiogenic mitogen selective for endothelial cells (EC) in endocrine glands [1].
• PK1 and PK2 and their receptors were localized to multiple cellular compartments, including glandular epithelial, stromal, and endothelial cells in the endometrium and endothelial and smooth muscle cells in the myometrium [12].
• Expression and regulation of the prokineticins (endocrine gland-derived vascular endothelial growth factor and Bv8) and their receptors in the human endometrium across the menstrual cycle [12].
• These AVIT family proteins target prokineticin receptors involved in the sensitization of nociceptors and gastrointestinal smooth muscle activation [13].
• Using isolated rat stomach fundus or guinea-pig ileum organ bath preparations we have shown that the prototypical ACTX-Hvf17, at concentrations up to 1muM, did not stimulate smooth muscle contractility, nor did it inhibit contractions induced by human PK1 (hPK1) [13].

Associations of PROK1 with chemical compounds

• Treatment with 1 microM ( micromol/liter(-1)) progesterone resulted in 2.91 +/- 0.75-fold elevation in PK1 expression, compared with controls (P < 0.05) [12].
• EG-VEGF/PK1 transcript was found in PCa, in CPEC, in EPN, and in LNCaP, whereas it was detected at low level in NP and in NPEC [4].
• In in vitro endometrial cell culture, EG-VEGF mRNA was detected in endometrial cells only in the presence of steroids, suggesting that EG-VEGF expression is highly dependent on the steroid hormones [3].
• EG-VEGF/PK1 was absent in androgen-independent PC3 and DU-145 cell lines [4].
• The t1/2 for oral calcitriol was 38 +/- 14 h for PK1 and 30 +/- 4 h for PK2 (not significant (NS)) [14].
• COX-2 mRNA and protein expression, and prostaglandin synthesis, were elevated in response to treatment with PROK1 [15].

Physical interactions of PROK1

• Consistent with such an expression pattern, the human EG-VEGF gene promoter has a potential binding site for steroidogenic factor (SF)-1, a pivotal element for steroidogenic-specific transcription [16].

Regulatory relationships of PROK1

• Furthermore, a FLIPR Ca2+ flux assay using HEK293 cells expressing prokineticin receptors showed that ACTX-Hvf17 fails to activate or block hPK1 or hPK2 receptors [13].
• Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization [8].

Other interactions of PROK1

• Thrombin, like hypoxia, also induced an opposite effect on VEGF and EG-VEGF/PK-1 [1].
• Quantitation of microvessel density (MVD) and semi-quantitation of VEGF, Ang2, ephrinB2 and EG-VEGF expression were analyzed to find the relations [17].
• These suggest that the antiapoptotic effect of PK-1 on LEC may be mediated via PK-R2 [18].
• Similar to VEGF, EG-VEGF possesses a HIF-1 binding site, and its expression is induced by hypoxia [7].
• Also, EG-VEGF expression correlates with vascularity in the polycystic ovary syndrome, a leading cause of infertility [16].

Analytical, diagnostic and therapeutic context of PROK1

• To investigate this, endometrial tissue was treated with 1 microM (micromol/liter(-1)) progesterone for 24 h, and PK1 expression was assessed by quantitative RT-PCR [12].
• Immunohistochemistry analysis showed that EG-VEGF is predominantly expressed in the glandular epithelial cells and its expression is dynamic during the menstrual cycle with a peak expression at the mid-luteal phase [3].
• We also found that EG-VEGF transcripts are up-regulated in all the peri-implantation endometrial samples from the patients after the ovulating dose of human chorionic gonadotropin in gonadotropin-stimulated cycles and patients receiving hormone replacement therapy [3].
• Using immunohistochemistry, Western blot, and RT-PCR, we determined the expression of EG-VEGF/PK1 in normal prostate (NP) and malignant prostate tissues (PCa), in epithelial cell primary cultures from normal prostate (NPEC) and malignant prostate (CPEC) and in a panel of prostate cell lines [4].
• Molecular cloning and characterization of prokineticin receptors [19].

References