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Validation of Serine/Threonine Protein Phosphatase As the Herbicide Target Site of Endothall ⇑ Joanna Bajsa, Zhiqiang Pan, Franck E

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Validation of Serine/Threonine Protein Phosphatase As the Herbicide Target Site of Endothall ⇑ Joanna Bajsa, Zhiqiang Pan, Franck E Pesticide Biochemistry and Physiology 102 (2012) 38–44 Contents lists available at SciVerse ScienceDirect Pesticide Biochemistry and Physiology journal homepage: www.elsevier.com/locate/pest Validation of serine/threonine protein phosphatase as the herbicide target site of endothall ⇑ Joanna Bajsa, Zhiqiang Pan, Franck E. Dayan, Daniel K. Owens, Stephen O. Duke USDA, ARS Natural Products Utilization Research Unit, University, MS 38677, USA article info abstract Article history: Endothall, an older commercial herbicide, and cantharidin, a natural product from the blister beetle (Epic- Received 4 October 2011 auta spp.), are close chemical analogues. A comparison of the effect of endothall and cantharidin on plants Accepted 20 October 2011 revealed a similarity in their level of phytotoxicity on both Arabidopsis thaliana and Lemna paucicostata. Available online 29 October 2011 Cantharidin is a potent inhibitor of animal serine/threonine protein phosphatases. Protein phosphatases and kinases maintain a sensitive balance between phosphorylated and dephosphorylated forms of pro- Keywords: teins playing important roles in signal transduction pathways. In this study, we found endothall and can- Cantharidin tharidin to both completely inhibit plant serine/threonine protein phosphatases, and their relative Endothall inhibitory activities were similar to their relative phytotoxicities. Both compounds acted as slow, irre- Lemna paucicostata Serine/threonine protein phosphatase versible inactivators of the serine/threonine protein phosphatase activities. Transcription of several genes determined to be affected by the inhibition of these protein phosphatases by cantharidin in A. thaliana by transcriptome analyses were affected similarly by endothall, but in a more pronounced way. Therefore, the molecular target site of endothall in plants is similar to that of cantharidin in animals, namely, ser- ine/threonine protein phosphatases responsible for regulating an array of biochemical processes. This mode of action is unlike any other commercial herbicide. Published by Elsevier Inc. 1. Introduction aphrodisiac associated with human poisonings [11,12].Itis currently being investigated as an anticancer drug lead [13]. In ani- Endothall (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid, mals, cantharidin is a strong inhibitor of serine/threonine protein Fig. 1) was introduced in the 1950s, yet it is one of the few herbi- phosphatases (PPs) [14], a broad class of PPs associated with sig- cides still listed as having an unknown mode of action [1,2].Ina naling and control of numerous cellular processes in many organ- chemical class of its own, endothall induces symptoms similar to isms (e.g., [15]). The catalytic domain of all PP subfamilies is highly chilling injury on the foliage of treated plants and ultimately conserved in animals, plants and protozoans [16]. Inhibitors, such results in severe growth inhibition [2]. Investigations on the mode as cantharidin and endothall, bind to a hydrophobic pocket of the of action of endothall reported effects on mRNA [3] and protein [4] PP active site. According Bertini et al. [17], two metal ions (Mn synthesis. Additionally, endothall causes membrane dysfunction and/or Zn) and the amino acids Tyr272, Val429, Phe260, Gln242, [5], and the WSSA Herbicide Handbook suggests that its action Arg89 and Arg214 are involved in the binding of these compounds may initiate at the membrane level [2]. However, loss of mem- in the human member of subfamily PP5. Endothall has two binding brane integrity can occur in plants exposed to herbicides with conformations: one similar to cantharidin’s orientation and a modes of action involving a wide array of molecular target sites second rotated by ca. 120°. The structural similarity between [6,7]. The primary target site of endothall in plants has remained endothall and cantharidin has been apparent to animal scientists elusive for many years. and similar mechanisms of action on animal serine/threonine PPs Endothall is a close analog of cantharidin (Fig. 1) from the blis- has been confirmed (e.g., [18]). ter beetle (Epicauta spp.) and the Spanish fly (Lytta vesicatoria). Scientists often use herbicides as molecular probes to study Some insects accumulate up to 5% of their dry weight of this natu- plant biochemical processes [19]. Endothall has recently been used ral defense terpenoid. Cantharidin has had various uses as a phar- to manipulate serine/threonine PP activity and investigate a num- maceutical over the years (e.g., [8–10]), and is infamous as an illicit ber of plant processes including disease resistance [20–24], metal ion toxicity [25,26], apoptosis [27], and regulation of anthocyanin biosynthesis [28]. Endothall strongly inhibits alfalfa serine/ Abbreviation: PP, protein phosphatase. ⇑ Corresponding author. Fax: +1 662 915 1036. threonine PP2A (PP2A) activity, as well as serine/threonine PP1 E-mail address: [email protected] (S.O. Duke). (PP1) to a lesser degree, which is accompanied by a profound effect 0048-3575/$ - see front matter Published by Elsevier Inc. doi:10.1016/j.pestbp.2011.10.007 J. Bajsa et al. / Pesticide Biochemistry and Physiology 102 (2012) 38–44 39 100 lmol mÀ2 sÀ1 PAR. For RNA and protein preparations, twelve-day-old seedlings were sprayed with the I30 concentration (concentration required to reduce chlorophyll content by 30% two days after treatment) of cantharidin (200 lM). Endothall was used at the same concentration. A. thaliana shoots were harvested 2, 10, and 24 h after spraying. Each experiment (time point) had three independent replicates of both treated and untreated (con- trol) samples. Fig. 1. Structures of endothall, cantharidin and cantharidic acid. Duckweed (Lemna paucicostata (L.) Hegelm.) bioassays were con- ducted as previously described [35]. L. paucicostata stocks were grown on modified Hoagland media. The media contained: on plant cell coordination of chromosomal and microtubule events À1 À1 À1 1515 mg L KNO3, 680 mg L KH2PO4, 492 mg L MgSO4.7H2O, during mitosis [29]. Tresch et al. [30] recently connected the inhi- À1 À1 À1 20 mg L Na2CO3, 1180 mg L Ca(NO3)2Á4H2O, 0.5 mg L H3BO3, bition of serine/threonine PPs by endothall to its pronounced ef- À1 À1 À1 0.05 mg L ZnSO4, 0.12 mg L Na2MoO4, 0.47 mg L MnCl2, fects on the plant cell cycle, which were similar to phenotypic À1 À1 À1 0.025 mg L CoCl2, 0.025 mg L CuSO4, 18.355 mg L Fe-EDTA. effects on plants with a mutant regulatory subunit (TON2) of a pro- The medium was adjusted to pH 5.5 with 1 M NaOH and then filter tein phosphatase (PP2A) in Arabidopsis thaliana. However, the phy- sterilized through a 0.2 lm sterile filter. All of the L. paucicostata totoxicity of endothall was not directly compared to its effect on used in these studies originated from a single L. paucicostata colony serine/threonine PP activity. We previously reported that canthar- (an aggregate of one mother and two daughter fronds) to assure idin was highly phytotoxic, apparently due to its effects on plant genetic uniformity. For the tests, plants were taken while still in serine/threonine PPs [31,32]. Herein, we validate the relationship exponential growth from a 4 to 5-day-old stock culture. between the herbicidal activity of endothall and inhibition of ser- Each concentration of a compound was tested in three repli- ine/threonine PPs supporting this data with an analysis of the com- cates. If required, the pH of the media was adjusted to 5.6 after pound’s effects on the expression of selected A. thaliana gene adding test chemicals. Both the initial screening and replicate ser- transcripts. ies tests were conducted in an incubator (Model #CU-36L, Percival Scientific, Boone, IA, USA) with white light (94 lEmÀ2 sÀ1) using 2. Materials and methods non-pyrogenic polystyrene sterile six-well plates (CoStar 3506, Corning Inc., Corning, NY, USA) with a lid. Each well contained 2.1. Chemicals 4950 lL of the Hoagland media plus 50 lL of water, or the solvent (as control), or the appropriate concentration of the compound dis- Technical grade endothall, cantharidin and all other chemicals solved in a suitable solvent. The final concentration of the solvent for the experiments were obtained from Sigma–Aldrich (St. Louis, was therefore 1% by volume. Each well was inoculated with two, MO, USA), with the exception of Tween 20 (Fisher Scientific, Pitts- three-frond colonies of approximately the same size. The selected burgh, PA, USA) and Murashige and Skoog (MS) basal salt mixture colonies had a ‘‘Mickey Mouse’’ appearance, where the developing (Phytotechnologies Laboratories, Shawnee Mission, KS, USA). daughter fronds were significantly smaller and still attached to the maternal frond. Total frond area per well was recorded by the im- 2.2. Culture and treatment of plants age-analysis-system Scanalyser (LemnaTec, Würselen, Germany) once per day from day 0 to day 7. Wild-type A. thaliana Columbia ecotype was grown on MS med- ium, five seedlings per well of a six-well plate at 24 °C and under constant light intensity of 100 lmol mÀ2 sÀ1 PAR. Twelve-day-old 2.3. Protein phosphatase assays seedlings were sprayed using chromatography sprayers (VWR) with a range of endothall or cantharidin concentrations in solution One gram of frozen plant material was ground in a mortar and of 0.1% acetone and 0.15% Tween 20 per container. Controls were pestle and suspended in 25 mM Tris-HCl pH 7.0%, 0.1% b-mercap- sprayed with a solution of 0.1% acetone and 0.15% Tween 20 solu- toethanol, 1 mM EDTA, 1 mM benzamidine, and 0.05% Tween 20 tion. The spray solution was applied to cover the leaf tissue and plant protease inhibitors cocktail (Sigma–Aldrich). The tissue entirely. Two days after spraying, shoots of the seedlings were har- was homogenized with a Polytron instrument (PT 3100, Kinemat- vested and chlorophyll content was determined by the method of ica AG, Littau-Lucerne, Switzerland) and centrifuged at 17,500g for Hiscox and Israelstam [33].
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