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POST-TRANSCRIPTIONAL REGULATION IN KINETOPLASTIDS 81 shock protein (HSP) genes of kinetoplastids were easy to find through high sequence conservation with other HSP genes, and seemed to be ideal candidates for identification of inducible RNA polymerase II promoters. The response to heat shock ought to be biologically relevant, as parasites in the mammalian host can cause fever, and the insect forms are subjected to both variations in environmental temperature within the insect and a temperature rise of up to 10°C upon injection into a mammalian host. Heat shock treatments of these magnitudes have therefore been used to analyse HSP expression in kinetoplastids: for example, a switch from 37°C to 42°C to mimic fever, and elevations from 25°C or 27°C to 35°C to mimic the transfer of insect forms to the skin of a mammalian host. The first candidates to be investigated were the HSP70 genes of T. brucei and Leishmania. These are arranged as polycistronically transcribed tandem repeats, and the levels of RNA were indeed mildly elevated upon heat shock. It was therefore hoped that there would be a promoter between each gene or, failing that, one promoter upstream of the cluster. Rather poor sequence similarities with the controlling promoter elements from higher eukaryotes were pointed out with enthusiasm. But in the end – as in all other searches for RNA polymerase II promoters upstream of protein-coding genes – it became clear that no promoters were there. Meanwhile, additional HSP genes were found. Expression of mitochondrial HSP60 has been little investigated (although it is an excellent mitochondrial marker protein and shows developmental regulation in T. brucei) but Leishmanial HSP85 has been analysed extensively. There is evidence from T. brucei that mRNA trans-splicing is disrupted by heat shock in bloodstream trypanosomes, but the HSP70 mRNAs seemed little affected. Both HSP70 and HSP85 (sometimes also called HSP83) mRNAs may be more stable at high temperatures than other RNAs, and there is evidence from L. amazonensis that HSP83 genes are also preferentially translated during heat shock. In L. infantum, there are six HSP70 genes arranged as a tandem repeat. Nearly all the RNA comes from gene 6, but only expression from gene 1–5 mRNAs was increased by heat shock. In all cases investigated, the sequences responsible have been shown to lie in the 3-untranslated region. But it is most unlikely that the regulation of HSP70 or HSP83 mRNA levels or translation has any biological relevance, as no-one has ever shown any changes in total HSP70 or HSP83 protein levels as a consequence of heat shock. HSP70 and HSP83 each make up between 2% and 3% of the total protein in unstressed Leishmania promastigotes, which is presumably sufficient to protect against physiological stresses. The most interesting HSP found so far is HSP100 from L. major and L. donovani. This is upregulated during heat shock of promastigotes, and during differentiation of promastigotes into amastigotes; gene replacement experiments indicate that it plays a role in parasite virulence. Degradation and translation of the EP mRNAs The EP and GPEET genes illustrate several aspects of gene regulation in trypanosomes (Figure 4.4). Regulation of EP transcription was studied by inserting a CAT reporter gene, bearing a 3-untranslated region that gave constitutive expression, into the EP locus (Figure 4.5A). Expression of the reporter was roughly 10-fold higher in procyclic forms than in bloodstream forms, indicating that transcription was regulated 10-fold. But EP RNA is extremely abundant in procyclics, and virtually undetectable in bloodstream forms, so the transcriptional MOLECULAR BIOLOGY
82 POST-TRANSCRIPTIONAL REGULATION A Bloodstream CAT EP2 Procyclic CAT 10 B Bloodstream Procyclic AAA 11 AAA 100 C D Deadenylation 3 A 5 m AAA 0 10 20 30 40 0 Minutes after Actinomycin D 5 3 AAA TTT E 3-UTR destruction 3 5 m A 0 10 20 30 40 0 Minutes after Actinomycin D A FIGURE 4.5 Experiments to determine the mechanism of EP regulation and mRNA degradation. MOLECULAR BIOLOGY
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Molecular Medical Parasitology
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Molecular Medical Parasitology Edit
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Contents List of contributors Prefa
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List of contributors Mark Blaxter,
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LIST OF CONTRIBUTORS ix Richard. J.
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Preface Parasitology was born as th
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S E C T I O N I MOLECULAR BIOLOGY
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C H A P T E R 1 Parasite genomics M
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TABLE 1.1 Parasite genomes: genome
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GENERATING GENOMICS DATA 7 differen
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GENERATING GENOMICS DATA 9 TABLE 1.
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GENERATING GENOMICS DATA 11 called
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GENERATING GENOMICS DATA 13 200 000
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BIOINFORMATICS AND THE ANALYSIS OF
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THE POST-GENOMICS ERA, AND THE OTHE
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THE PARASITES AND THEIR GENOMES 19
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FURTHER READING 27 treated with a d
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C H A P T E R 2 RNA processing in p
Page 44 and 45: TRANS-SPLICING 31 cis trans Exon 1
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Page 50 and 51: RNA EDITING 37 P AAAA... AAAA... AA
Page 52 and 53: RNA EDITING 39 entire transcript re
Page 54 and 55: RNA EDITING 41 5 Editing block C Ed
Page 56 and 57: RNA EDITING 43 microscopy) approach
Page 58 and 59: FURTHER READING 45 Nilsen, T.W. (19
Page 60 and 61: C H A P T E R 3 Transcription Arthu
Page 62 and 63: UNUSUAL MODES OF TRANSCRIPTION IN T
Page 64 and 65: CLASS I TRANSCRIPTION IN TRYPANOSOM
Page 70 and 71: CLASS II TRANSCRIPTION OF PROTEIN C
Page 72 and 73: SL RNA AND U snRNA GENE TRANSCRIPTI
Page 78 and 79: FURTHER READING 65 and switching in
Page 80 and 81: C H A P T E R 4 Post-transcriptiona
Page 82 and 83: POST-TRANSCRIPTIONAL REGULATION IN
Page 100 and 101: FURTHER READING 87 inhibition, it m
Page 102 and 103: C H A P T E R 5 Antigenic variation
Page 104 and 105: ANTIGENIC VARIATION AT THE STRUCTUR
Page 106 and 107: ANTIGENIC VARIATION AT THE STRUCTUR
Page 108 and 109: VSG Signal sequence Amino-terminal
Page 110 and 111: GENETICS OF ANTIGENIC VARIATION 97
Page 116 and 117: IMMUNE RESPONSES TO TRYPANOSOME INF
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Page 122 and 123: FURTHER READING 109 ACKNOWLEDGEMENT
Page 124 and 125: C H A P T E R 6 Genetic and genomic
Page 126 and 127: ‘FORWARD’ VS. ‘REVERSE’ GEN
Page 128 and 129: EXAMPLES OF ‘FORWARD’ GENETIC A
Page 130 and 131: EXAMPLES OF ‘FORWARD’ GENETIC A
Page 132 and 133: REVERSE GENETICS AND LEISHMANIA VIR
Page 134 and 135: VALIDATION OF CANDIDATE VIRULENCE G
Page 136 and 137: S E C T I O N II BIOCHEMISTRY AND C
Page 138 and 139: C H A P T E R 7 Energy metabolism P
Page 140 and 141: SUBCELLULAR ORGANIZATION OF AMITOCH
Page 142 and 143: CELL MEMBRANE Fructose [b] Glucose
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STEPS OF AMITOCHONDRIATE CORE METAB
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ENZYMATIC DIFFERENCES BETWEEN AMITO
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ACTION OF NITROIMIDAZOLE DRUGS 135
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ENVOI 137 unambiguously reflect the
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FURTHER READING 139 Saavedra-Lira,
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THE EMBDEN-MEYERHOF-PARNAS (EMP) PA
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WHY DO TRYPANOSOMATIDAE HAVE GLYCOS
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FURTHER READING 153 for use in agri
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CARBOHYDRATE METABOLISM 155 as a hu
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158 ENERGY METABOLISM - APICOMPLEXA
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172 PROTEIN METABOLISM PROTEINS (1)
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174 PROTEIN METABOLISM the C-termin
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176 PROTEIN METABOLISM and also, to
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178 PROTEIN METABOLISM values rangi
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180 PROTEIN METABOLISM of the plasm
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182 PROTEIN METABOLISM in vivo, in
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184 PROTEIN METABOLISM PROLINE Poly
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186 PROTEIN METABOLISM CO 2 Dec-SAM
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188 PROTEIN METABOLISM a cMDH has b
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190 PROTEIN METABOLISM Urea ARGININ
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192 PROTEIN METABOLISM been describ
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194 PROTEIN METABOLISM absence of g
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198 PURINES AND PYRIMIDINES enable
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200 PURINES AND PYRIMIDINES provide
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202 PURINES AND PYRIMIDINES activit
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204 PURINES AND PYRIMIDINES physiol
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206 PURINES AND PYRIMIDINES Amitoch
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208 PURINES AND PYRIMIDINES their a
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210 PURINES AND PYRIMIDINES FIGURE
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214 PURINES AND PYRIMIDINES protein
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220 PURINES AND PYRIMIDINES in Plas
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222 PURINES AND PYRIMIDINES whereas
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226 TRYPANOSOMATID CARBOHYDRATES AF
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228 TRYPANOSOMATID CARBOHYDRATES In
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230 TRYPANOSOMATID CARBOHYDRATES po
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232 TRYPANOSOMATID CARBOHYDRATES LP
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234 TRYPANOSOMATID CARBOHYDRATES re
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236 TRYPANOSOMATID CARBOHYDRATES sc
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A. sAP COOH [T][T](S/T)(S/T)(S/T)SS
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240 TRYPANOSOMATID CARBOHYDRATES Cr
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242 INTRACELLULAR SIGNALING protein
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244 INTRACELLULAR SIGNALING FIGURE
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246 INTRACELLULAR SIGNALING 212.5 2
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248 INTRACELLULAR SIGNALING cycle.
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250 INTRACELLULAR SIGNALING V-H -A
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252 INTRACELLULAR SIGNALING domain)
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254 INTRACELLULAR SIGNALING the kno
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256 INTRACELLULAR SIGNALING from in
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258 INTRACELLULAR SIGNALING FIGURE
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260 INTRACELLULAR SIGNALING ESAG4 (
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262 INTRACELLULAR SIGNALING and ind
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264 INTRACELLULAR SIGNALING ATPase
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266 INTRACELLULAR SIGNALING G11XG
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268 INTRACELLULAR SIGNALING a diffe
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270 INTRACELLULAR SIGNALING rapid l
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272 INTRACELLULAR SIGNALING cells w
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274 INTRACELLULAR SIGNALING PfPPJ i
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276 INTRACELLULAR SIGNALING is cont
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278 PLASTIDS, MITOCHONDRIA, AND HYD
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298 HELMINTH SURFACES Important exc
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300 HELMINTH SURFACES protease inhi
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302 HELMINTH SURFACES volume, there
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304 HELMINTH SURFACES projecting si
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306 HELMINTH SURFACES schistosome t
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308 HELMINTH SURFACES re-establish
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310 HELMINTH SURFACES hepatic cells
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312 HELMINTH SURFACES lungs. Larvae
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314 HELMINTH SURFACES cuticle, whic
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316 HELMINTH SURFACES cuticle in th
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318 HELMINTH SURFACES mec-8 or sym-
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320 HELMINTH SURFACES current, when
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322 HELMINTH SURFACES The cuticle-h
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324 HELMINTH SURFACES are typically
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326 HELMINTH SURFACES or carrier pr
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328 HELMINTH SURFACES of tyrosine-b
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330 HELMINTH SURFACES blood. The ge
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332 HELMINTH SURFACES Mutations in
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334 HELMINTH SURFACES in the hypode
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336 HELMINTH SURFACES (including H-
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338 HELMINTH SURFACES Blaxter, M.L.
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340 ENERGY METABOLISM IN HELMINTHS
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360 NEUROTRANSMITTERS CO 2 H NH 2 G
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362 NEUROTRANSMITTERS TABLE 15.1 An
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364 NEUROTRANSMITTERS more arms tha
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366 NEUROTRANSMITTERS the surroundi
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368 NEUROTRANSMITTERS proteins requ
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370 NEUROTRANSMITTERS FIGURE 15.11
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372 NEUROTRANSMITTERS FIGURE 15.13
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374 NEUROTRANSMITTERS sensitivity t
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376 NEUROTRANSMITTERS TABLE 15.3 Cl
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378 NEUROTRANSMITTERS crossed the c
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380 NEUROTRANSMITTERS have been tes
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382 NEUROTRANSMITTERS C-terminals a
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384 NEUROTRANSMITTERS Davis and Str
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386 NEUROTRANSMITTERS Cephalic gang
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388 NEUROTRANSMITTERS myoexcitation
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390 NEUROTRANSMITTERS is phosphoryl
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392 NEUROTRANSMITTERS many other an
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398 DRUG RESISTANCE of some of the
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400 DRUG RESISTANCE It is now estim
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402 DRUG RESISTANCE is again assume
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404 DRUG RESISTANCE An alternative
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406 DRUG RESISTANCE clinical eviden
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408 DRUG RESISTANCE FIGURE 16.4 Fol
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410 DRUG RESISTANCE Using similar s
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412 DRUG RESISTANCE whether these r
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414 DRUG RESISTANCE FIGURE 16.5 Str
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416 DRUG RESISTANCE FIGURE 16.6 Try
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418 DRUG RESISTANCE has permitted e
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420 DRUG RESISTANCE FIGURE 16.7 Dru
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422 DRUG RESISTANCE near future. Th
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424 DRUG RESISTANCE million new inf
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426 DRUG RESISTANCE some 50 million
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428 DRUG RESISTANCE pharynx, the bo
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430 DRUG RESISTANCE efforts for glo
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432 DRUG RESISTANCE and resistance
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434 MEDICAL IMPLICATIONS TABLE 17.1
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436 MEDICAL IMPLICATIONS TABLE 17.1
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438 MEDICAL IMPLICATIONS transmissi
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440 MEDICAL IMPLICATIONS H 2 C H H
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442 MEDICAL IMPLICATIONS parasites
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444 MEDICAL IMPLICATIONS neuropsych
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446 MEDICAL IMPLICATIONS of toxic f
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448 MEDICAL IMPLICATIONS Future con
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450 MEDICAL IMPLICATIONS Melarsopro
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452 MEDICAL IMPLICATIONS prevention
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454 MEDICAL IMPLICATIONS resulting
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456 MEDICAL IMPLICATIONS for S. ste
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458 MEDICAL IMPLICATIONS are though
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460 MEDICAL IMPLICATIONS FIGURE 17.
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462 MEDICAL IMPLICATIONS Marr, J.J.
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464 INDEX Aldolase, 143 Plasmodium
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466 INDEX Ascofuranone, 143 ASCUT-1
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468 INDEX Cnidarians, RNA trans-spl
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470 INDEX Entamoeba, 125 Ca 2 metab
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472 INDEX Glucose-6-phosphate dehyd
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474 INDEX Ivermectin, 398, 427, 455
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476 INDEX Maduramicin, 412 Major va
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478 INDEX Nitric oxide: neurotransm
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480 INDEX calcium-binding proteins,
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482 INDEX Pyrimidine transport, 200
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484 INDEX Succinate:rhodoquinone ox
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486 INDEX genome, 21 survey sequenc
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488 INDEX U small nuclear RNA (snRN
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