Genetic Mechanisms of Age Regulation of Human Blood Coagulation Factor IX

Kurachi, Sumiko; Deyashiki, Yoshihiro; Takeshita, Junko; Kurachi, Kotoku

doi:10.1126/science.285.5428.739

Cited by 74 publications

(109 citation statements)

References 29 publications

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“…The presence of ASE did not have any significant effect on transient hPC expression in HepG2 cells, while the presence of AIE in hPC minigenes lowered their transient expression activities by ϳ30% (Fig. 2B) in agreement with our previous observations on hFIX minigenes containing AIE (12).…”

Section: Age-related Expressionsupporting

confidence: 81%

“…Human FIX minigenes, ASEmin/Ϫ416FIXm1 and AIE/Ϫ416FIXm1/ASE, were constructed by inserting a single copy of the 17-bp minimum ASE sequence (ASEmin: nt Ϫ795 through Ϫ779 of the hFIX gene) or a copy of the above AIE into minigenes Ϫ416FIXm1 and Ϫ416FIXm1/ASE (12) at the 5Ј-end SphI site, respectively. Minigene Ϫ802FIXm1/mDR was constructed by inserting a 106-bp dinucleotide repeat sequence of the mFIX gene (nt ϩ2018 through ϩ2123 of the mFIX cDNA) (18) at the BamHI site of Ϫ802FIXm1 (12). PCR-amplified sequences and ligation sites of all of the new constructs were confirmed by automated dideoxy sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…Horseradish peroxidase-linked goat anti-rabbit IgG was purchased from Invitrogen. Antibodies used for hFIX-specific enzyme-linked immunosorbent assay (ELISA) were described previously (12). Medium, fetal calf serum, penicillin, and streptomycin for mammalian cell cultures were obtained from Invitrogen.…”

Section: Methodsmentioning

confidence: 99%

“…Circulatory hPC or hFIX levels of transgenic mice at each age point were quantified by duplicated ELISA. Human FIX ELISA was applied as previously described (12). To minimize experimental fluctuations from assay to assay in the longitudinal analysis, overlapped serum samples from the previous assay group were included in each assay.…”

Section: Methodsmentioning

confidence: 99%

“…In comparison with hFIX, the plasma levels of hPC showed only marginal age-associated changes (3,11). We previously identified two genetic elements, ASE and AIE (renamed from AE 5Ј and AE 3Ј, respectively), which are required for age-related stability and increase of hFIX expression, respectively (12). ASE, originally identified as a footprint sequence between nucleotide (nt) Ϫ802 and nt Ϫ784 of the hFIX gene, has a core sequence, GAGGAAG, matching the transcriptional factor PEA-3 consensus sequence ((G/C)AG-GA(A/T)G) (13,14).…”

mentioning

confidence: 99%

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Genetic Mechanisms of Age Regulation of Protein C and Blood Coagulation

Zhang¹,

Kurachi

2002

Journal of Biological Chemistry

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Blood coagulation activity in humans increases with age. We previously identified two genetic elements, agerelated stability element (ASE; GAGGAAG) and age-related increase element (AIE; unique stretch of dinucleotide repeats), which were responsible for age-related stable and increasing expression patterns, respectively, and together recapitulated normal age regulation of the human factor IX (hFIX) gene. Here we report the ageregulatory mechanisms of human anticoagulant protein C (hPC), which shows an age-stable pattern of circulatory levels. The murine protein C gene showed an agerelated stable expression pattern in general agreement with that of the hPC. Through longitudinal analyses of transgenic mice carrying hPC minigenes, the hPC gene was found to have a functional age-related stability element (hPC ASE; CAGGAAG) in the 5-upstream proximal region but was found to lack any age-related increase element. Three other ASE-like sequences present in the hPC gene, GAGGAAA and (G/C)AGGATG, also bound nuclear proteins but were not active in the age regulation of the hPC gene. Functional hPC ASE and hFIX ASE were apparently generated through convergent evolution, and hFIX ASE can fully substitute for the hPC ASE in conferring age-related stable expression pattern of the hPC gene. In the presence of the hPC ASE, hFIX AIE can convert the age-stable expression pattern of the hPC gene to a hFIX-like age-related increase pattern. These results support the universality of ASE and AIE functions across different genes. Clearance of hPC protein from the circulation was not significantly affected by age. We now have established the basic mechanisms responsible for the age-related increase of blood coagulation activity.

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Section: Age-related Expressionsupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Genetic Mechanisms of Age Regulation of Protein C and Blood Coagulation

Zhang¹,

Kurachi

2002

Journal of Biological Chemistry

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Christmas Factor

Stafford¹,

Monahan²

2002

Wiley Encyclopedia of Molecular Medicine

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Unintended benefit of anabolic steroid use in hemophilia B leiden

et al. 2011

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Darinaparsin is a novel organic arsenic compound that is being developed to improve the efficacy and therapeutic index of arsenic as an antineoplastic agent. It has activity in preclinical models of hematological malignancies and we set out to test it in patients with refractory lymphoma. In this multicenter, Phase II trial, patients with relapsed or refractory Hodgkin (HL) and non-Hodgkin lymphoma (NHL) were treated with darinaparsin 300 mg/m 2 intravenously daily for five consecutive days every 28 days, for up to six cycles. The primary endpoint was the overall response rate. Twenty-nine heavily pretreated patients with lymphoma (22 with NHL and 7 with HL) were enrolled. There was one complete response (CR), one unconfirmed CR (CRu), three partial responses (PRs), and four with stable disease (SD), with an overall response rate of 17% (95% confidence interval (CI) 6-36%). Among the seven patients with peripheral T-cell lymphoma (PTCL), there was one CR, one CRu, and two with prolonged SD. The most common toxicities were fatigue, nausea, diarrhea, and anemia. Darinaparsin was safe and showed preliminary activity in this heavily pretreated population of relapsed/refractory lymphoma patients. Encouraging responses were seen in PTCL and further study in this subtype is planned. An estimated 74,030 people in the United States are diagnosed with HL or NHL every year with a global disease burden of approximately 350,000 new cases per year [1,2]. Major advances have been made over the last few decades in the treatment of these disorders in the form of combination chemotherapy, monoclonal antibody therapy, and stem cell transplantation [3-5], resulting in cure for a substantial proportion of cases. However, there remains a subgroup of patients who do not respond to standard therapy or relapse after an initial response. PTCL accounts for 7-10% of NHL cases and is a particularly unfavorable subtype [6]. Combination chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is the usual treatment approach for PTCL, but outcomes are generally poor even with more intensive regimens [7]. Darinaparsin (N-[S-(dimethylarsino)-N-L-gamma-glutamyl-L-cysteinyl]-glycine; S-dimethylarsino-glutathione, ZIO-101, Zinapar TM) is a novel organic arsenic molecule consisting of dimethylated arsenic conjugated to glutathione [8]. Darinaparsin achieves higher intracellular levels compared to inorganic arsenic trioxide (ATO), and has activity in vitro against leukemia, myeloma, lymphoma, and various solid tumor cell lines [9,10]. Darinaparsin's multifaceted mechanisms of action include disruption of mitochondrial functions, increase in reactive oxygen species (ROS), and effects on signal transduction. Darinaparsin induces cell cycle arrest and apoptosis and has potent anti-angiogenic activity [11]. Unlike ATO, darinaparsin lacks affinity for the ABCC1 efflux proteins and is cytotoxic to certain ATO-resistant cell lines [12]. While other arsenicals have been used clinically, particularly for the treatment of acute promye...

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Genetic Mechanisms of Age Regulation of Human Blood Coagulation Factor IX

Cited by 74 publications

References 29 publications

Genetic Mechanisms of Age Regulation of Protein C and Blood Coagulation

Genetic Mechanisms of Age Regulation of Protein C and Blood Coagulation

Christmas Factor

Unintended benefit of anabolic steroid use in hemophilia B leiden

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