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COORDINATE REGULATION OF ADENOSINE DEAMINASE, PURINE NUCLEOSIDE PHOSPHORYLASE AND TERMINAL DEOXYNUCLEOTIDYL 23 TRANSFERASE mRNA LEVELS BY PHORBOL ESTERS IN HUMAN L G.k' ard ~me2T. ~cott THYMOCYTES. a and U Wtinez-Valdez, Lb Ektr-iziW ~ernedyInstitute of The Hospital for Sick Children, Division of Inmunology memtolcgy hit memtolcgy /Rheumatology, Research Institute, Toronto, Ontario Qsm, Surrey. U.K. Lndcn 6 U.K. Canada. Phorbol esters caused reversible decrease in the levels of ter- Gcut patients are Imam to have risk factors which pmibpse to Msollar disease, hyprlipidaarda, hypertensim, obesity ard pmxdities minal deoxynucleotidyl transferase (TdT) and adenosine deaminase ircluiirg l)p A in mtim ard a hi& alcohol intake. (ADA) mRNAs and an increase in the level of purine nucleoside with hypn~13caarda phosphorylase (PNP) mRNA. The structural specificity of the In this study a saoring sysk has dmin which risk factors for Msollar phorbol esters affecting ADA, TdT and PNP mRNA levels correlates diseasemsoo~usirgscalesbasedmthe&tiveinportanceofthese with their effectiveness in the activation of protein kinase (?KC). factorsinthepakge2&3of~disease. The effect of phorbol esters on TdT and ADA mRNA levels is attributed to an apparent decrease in stability of their mRNAs. For each of 35 patients with prinary gcut a rk& saxe KB debmiwd ard each The changes observed in ADA, TdT and PNF mRNA levels closely patient has advisfd ard treated to his or her om risk factors. simulate the behaviour of these enzyme activities during T-cell Patients w seen every three nrnths, at which tirres their risk soores m differentiation in vivo. Moreover, similar changes in ADA, TdT recalollatedardfllrtheradvioegiventosee~therMsollar~rruldbe and PNP activities were observed in immature pre-B and T-lymphoid r-akei. cell lines expressing TdT activity. scores f'mn 2 15, with a value a en- the study of 8.4. The presence of high ADA and low PNP activities in immature Risk rang4 - mean 9 patient3 their by 3 or at cne or stage in follcw lymphocytes may have a role in maintaining balanced intracellular r&x& rk& soore m m up while 4 their rn by 3 or dGTP/dATP pools which are required for TdT activity (Cohen, A. irsrea?d m. Usirg paired t test.? to mrpare rM for the group after lengths of Collar up et al. J. Biol. Chem. ?58:12334). Expression of TdT activity is scores variw =re skqificant falls in risk sare at nrnths 3 9 (p 0.6 ard 0.W). a requirement for the diversification of immunoglobulin (Ig) and ard < < T-cell antigen receptor (TcR) genes. Thus, upon completion of Rese resllts shculd be seen in the rmtext of a srall study but suegest ht Ig and TcR gene rearrangement PKC activation may mediate the inkive cmselling my WiciaUy affect risk rn for Msollar disease programmed changes in these enzyme levels to those observed in in gout patients. mature lymphocytes. FUNGALBIONICB-A NEW CONCEPT OF THE ETIOLOGY STRUCTURAL CONSEQUENCES OF POINT MUTATIONS IN NINE OF GOUT AND HYPERURICEUIA. A.V. Costantlnl HUNAN HPRT VARIANTS. Beverly L. Davidson, Thomas 24 Univ of Calif School of Ued San Francisco &a 27 D. Palella, Shin Fujlmori, William N. ~~11~~. U.S.A./Uulticenter Fungalbionic Research University of Michigan. Department of Internal Project. Address all mail to European Office Medicine, Ann Arbor, Michigan-, USA. Am Uuehlbach 13, 7800 Freiburg, West Germany Fungalbionics implicates fungi and fungal metabolltes Complete deficiency of hypoxanthine guanine phosphoribosyl- as the cause of gout/hyperuricemia. The mechanlsms are transferase causes the Lesch-Nyhan Syndrome (LNS). Partial not the usual patterns of invasive-type mycoses nor of deficiency of HPRT causes severe, precocious gout. The mycotoxicoses, but rather incorporate occult features molecular basis for HPRT deficiency has been determined of both mechanisms. Gout and/or hyperurlcemia can be previously in this laboratory by amino acid sequence analysis induced in fowl by the mycotoxlns oosporein, ochratox- in three suhjects and by cloning of mutant cDNA sequences in In and by oosporein-produclng fungl. Gouty tophl have six subjects. In each case a single point mutation resulting been induced In primates by aflatoxin. Fungi produce in a single amino acid substitution was identified. The preformed uric acld, preformed urate crystals, lipo- structural consequences of these mutations were examined using proteins, glycosaminoglycans and glutamatcs, excess of secondary structure prediction techniques. The mutations in which are found in gout. Gouty tophi are granulomatous HPRT-London and HPRT-Yale abolish putative 8-turns while the and possess all of the features of delayed hypersensl- mutation in HPRT-Midland predicts an additional 8-turn. A tivlty. Giant cells in avian and human gouty tophi sequence predicted to be in random coil structure in WRT- contain asteroid bodies which are fungal In origin. Munich and HPRT-Ashville is replaced by 6-sheet structure and Fungal-like spherules have been found in avlan gouty a region of putative A-sheet in HPRT-Ann Arbor ia replaced by lesions; cultural and immunological electron micro- a-helix. The predicted structural consequences of the scopy studles are In progress. The findings in acute mutations in HPRT-Flint, HPRT-Kinston, and HPRT-Toronto were gout are those of an acute infection. All drugs used unremarkable using these techniques. in treatlng gout/hyperuricemia are antifungal. Grlseo- fulvln, an antifungal antlbiotlc, is as effective as colchlcine in gout. Both are antitubulins and arrest fungal cell division. Probenecid, allopurinol, cortl- costeroids, NSAIDS, possess antifungal activity. The fungalbionic concept gives a unitarian explanation of gout, hyperuricemia and related dlseases and findings. THE ACTIVITY OF AA-193, A HEW URICOSURIC AGENT, IN CEREBROSPINAL FLUID CYCLIC NUCLEOTIDE ALTERATIONS IN ANIMALS. Takashi Dan, Hiroshi KOQ, Etsuro Onuma, THE LESCH-NYHAN SYNDROME. N. Lawrence Edwards, Dept Haruko Tanaka, Haruhiko Sato and Bunya Aoki. Chugai of Medicine, Univ of Florida and VAMC, Gainesville, 25 Pharmaceutical Co., Ltd., Exploratory Research 28 Florida and Michael V. Johnston, and Faye S. Laboratories, Gotemba-shi, Shizuoka 412, Japan. Silverstein Dept of Neurology and Pediatrics, Univ of Xichigan, Ann Arbor, Michigan, USA. A new uricosuric agent, 5-chloro-7,8-dihydro-3-phenylfuro[2,3- Cyclic nucleotides in the central nervous system may have gl-l,2-benzisoxazole-7-carboxylic acid (AA-193) was compared with "first" messenger roles as well as the classic "second" aessenger other uricosurics in the rat, mouse and cebus monkey, because the effects. Such primary actions may include regulation of neuro- effects of those drugs were known to be highly species-dependent. transmitter synthesis, control of certain cellular movements and Probenecid and tienilic acid which in the human kidney block effects on both tropic and developmental processes. Low cyclic the reabsorption of filtered and secreted urate, increased the AMP (CAMP) levels are reported in spinal fluids (CSF) from pati- urate excretion in rats. But benzbromarone, an inhibitor of the ents with certain basal ganglion diseases, i.e. Parkinson's and latter reabsorption in man, did not have the uricosuric advanced Huntington's disease. Cyclic GMP (cm) in the CSF is act,ivity. Thus, the post-filtered reabsorption of urate is felt to reflect central cholinergic activity. In an effort co probably dominant in rats. We found that in rats AA-193 is the find a suitable biochemical marker of disease activity in the most potent uricosuric yet reported. In mice, probenecid not only Lesch-Nyhan syndrome (L-NS) we made serial measurements of cANP had so-called paradoxical actions but stimulated the urinary and cGMP on deproteinized CSF extracts using a radioimmunoassay. urate wasting after administration ol pyrazinamide. Aspirin also Three boys with L-NS at ages 29, 68, and 128 months had 5 CSF responded paradoxically. These data suggested that the renal determinations over the subsequent 40 months period. Seventeen transport system of urate in the mouse is similar to that in man. age-matched patients undergoing leukemia workup and showing no AA-193 as well as benzbromarone enhanced the urate excretion evidence of CNS disease were used as controls. The control group dose-dependently in normal condition, but the effects were had values of 1.4 t 0.6 pmollml for CAMP and 0.1 t 0.05 for cGMP. different in pyrazinamide-suppression tests in mice. In cebus The L-NS subjects had CAMP level of 4.3 t 2.1 and cGMP of 1.1 t monkeys, the uricosuri~ and hypouricemic effects of AA-193 were 0.7. The correlation (Pearson's) between CAMP and cGMP levels in more putent than those of probenecid and similar to those of the L-NS subjects was r = 0.83 and in the controls only 0.26. tienilic acid, but less than those of benzbromarone. These findings raise the possibility of an as yet undescribed CSF Benzbromzrone had a considerable role in post-secreted metabolite with caffeine-like activity in the L-NS spinal fluid raabsorption in the mokey. that may block cyclic nucleotide phosphodiesterase activity and Csnclusion: AA-19: is a new class of uricosuric agent that lead to CSF cyclic nucleotide elevations. controls the renal reabsorption of filtrat~durate particularly. .
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  • Metabolomics Identifies Pyrimidine Starvation As the Mechanism of 5-Aminoimidazole-4-Carboxamide-1- Β-Riboside-Induced Apoptosis in Multiple Myeloma Cells

    Metabolomics Identifies Pyrimidine Starvation As the Mechanism of 5-Aminoimidazole-4-Carboxamide-1- Β-Riboside-Induced Apoptosis in Multiple Myeloma Cells

    Published OnlineFirst April 12, 2013; DOI: 10.1158/1535-7163.MCT-12-1042 Molecular Cancer Cancer Therapeutics Insights Therapeutics Metabolomics Identifies Pyrimidine Starvation as the Mechanism of 5-Aminoimidazole-4-Carboxamide-1- b-Riboside-Induced Apoptosis in Multiple Myeloma Cells Carolyne Bardeleben1, Sanjai Sharma1, Joseph R. Reeve3, Sara Bassilian3, Patrick Frost1, Bao Hoang1, Yijiang Shi1, and Alan Lichtenstein1,2 Abstract To investigate the mechanism by which 5-aminoimidazole-4-carboxamide-1-b-riboside (AICAr) induces apoptosis in multiple myeloma cells, we conducted an unbiased metabolomics screen. AICAr had selective effects on nucleotide metabolism, resulting in an increase in purine metabolites and a decrease in pyrimidine metabolites. The most striking abnormality was a 26-fold increase in orotate associated with a decrease in uridine monophosphate (UMP) levels, indicating an inhibition of UMP synthetase (UMPS), the last enzyme in the de novo pyrimidine biosynthetic pathway, which produces UMP from orotate and 5-phosphoribosyl- a-pyrophosphate (PRPP). As all pyrimidine nucleotides can be synthesized from UMP, this suggested that the decrease in UMP would lead to pyrimidine starvation as a possible cause of AICAr-induced apoptosis. Exogenous pyrimidines uridine, cytidine, and thymidine, but not purines adenosine or guanosine, rescued multiple myeloma cells from AICAr-induced apoptosis, supporting this notion. In contrast, exogenous uridine had no protective effect on apoptosis resulting from bortezomib, melphalan, or metformin. Rescue resulting from thymidine add-back indicated apoptosis was induced by limiting DNA synthesis rather than RNA synthesis. DNA replicative stress was identified by associated H2A.X phosphorylation in AICAr-treated cells, which was also prevented by uridine add-back.