Disrupting the Pairing Between let-7 and Hmga2 = Enhances Oncogenic Transformation -- Mayr et al. 315 (5818): 1576 -- = Science

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Originally published in = Science Express=20 on 22 February 2007
Science 16 March = 2007:
Vol. 315.=20 no. 5818, pp. 1576 - 1579
DOI: = 10.1126/science.1137999

Prev | Tab= le=20 of Contents | Next=20

Reports

Disrupting the Pairing Between let-7 and Hmga2 = Enhances=20 Oncogenic Transformation
Christine=20 Mayr,¹ Michael T. = Hemann,²=20 David P. Bartel¹^*<=
/A>=20
MicroRNAs (miRNAs) are $3D~=20$ 22-nucleotide RNAs=20 that can pair to siteswithin messenger RNAs to specify = posttranscriptional repressionof these messages. = Aberrant=20 miRNA expression can contributeto tumorigenesis, but = which of=20 the many miRNA-target relationshipsare relevant to = this=20 process has been unclear. Here, we reportthat = chromosomal=20 translocations previously associated with humantumors = disrupt=20 repression of High Mobility Group A2 (Hmga2)⁼by=20 let-7 miRNA. This disrupted repression promotes=20 anchorage-independentgrowth, a characteristic of = oncogenic=20 transformation. Thus,losing miRNA-directed repression = of an=20 oncogene provides a mechanismfor tumorigenesis, and = disrupting=20 a single miRNA-target interactioncan produce an = observable=20 phenotype in mammalian cells.
¹ Howard Hughes Medical Institute = and=20 Department of Biology, Massachusetts Institute of Technology, and=20 Whitehead Institute for Biomedical Research, 9 Cambridge Center,=20 Cambridge, MA 02142, USA.
² Center for Cancer = Research,=20 Massachusetts Institute of Technology, Cambridge, MA 02139, USA. =

^* To whom correspondence should be addressed. = E-mail: dbartel{at}wi.mit.edu
Hmga2 codes for a small, nonhistone, = chromatin-associated=20 proteinthat has no intrinsic transcriptional activity = but can=20 modulatetranscription by altering the chromatin = architecture=20 (1,=20 2).⁼²⁰Hmga2 is primarily expressed in undifferentiated=20 proliferatingcells during embryogenesis and in a wide = variety=20 of benign andmalignant tumors (3=966).=20 In many of these tumors, a chromosomaltranslocation at = 12q15=20 truncates the human HMGA2 open readingframe = (ORF),=20 typically retaining the three DNA-binding domainsof = HMGA2=20 while replacing the spacer and the acidic domain atthe = C=20 terminus by any of a wide variety of ectopic sequences⁼(3=965,=20 7=96<= I>10)=20 (SOM text) (Fi= g.=20 1A). The loss of theC-terminal region is nearly = always=20 presumed to be the causeof oncogenic transformation. = However,=20 the translocations alsoreplace the 3' untranslated = region (3'=20 UTR), and large fragmentsof the Hmga2 3' UTR = confer=20 repression to luciferase reporters,which has led to = the idea=20 that transformation might be causedby the loss of = repressive=20 elements in the UTRs (<= I>11).=20 Indeed,chromosomal rearrangements in some tumors leave = the ORF=20 intactbut disrupt the 3' UTR, and this is associated = with=20 overexpressionof the wild-type Hmga2 protein (3,=20 4,=20 <= I>10).=20 Moreover, transgenicmice overexpressing wild-type = Hmga2 have=20 similar phenotypesto those expressing the truncated = protein;=20 both develop abdominallipomatosis, then lymphomas, = pituitary=20 adenomas, and lung adenomas(2,=20 <= I>12,=20 <= I>13).⁼²⁰

Fig. 1. Chromosomal = translocations involving HMGA2, and the = influence of=20 let-7 on protein expression. (A) = Translocations=20 involving HMGA2 and numerous translocation = partners (3=96<= I>10)=20 (SOM text). These translocations generate a truncated=20 HMGA2 mRNA lacking the let-7 = complementary sites=20 of the wild-type mRNA and are associated with the = indicated=20 tumors. In its 3' UTR, human HMGA2 has seven=20 let-7 complementary sites, all of which are = conserved=20 in the mouse, rat, dog, and chicken (<= I>14).=20 A_(n), polyadenylate tail. (B) RNA = blot=20 detecting let-7 RNA in different cell lines. = The blot=20 was reprobed for U6 small nuclear RNA (snRNA), and=20 let-7 signal normalized to that of U6 is = indicated.=20 (C) Western blot monitoring endogenous Hmga2 48 = hours=20 after transfection of F9 cells with the indicated = miRNA=20 duplex. The blot was also probed for=20 glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and = the=20 normalized Hmga2 signal is indicated. (D) = Western blot=20 monitoring endogenous Hmga2 at 24 (left) and 48 = (right) hours=20 after transfection of NIH3T3 cells with the indicated=20 2'-O-methyl oligonucleotide (2'-O-Me). = The blot=20 was probed also for GAPDH, and the normalized Hmga2 = signal is=20 indicated. [V= iew=20 Larger Version of this Image (45K GIF = file)]=20 =

The Hmga2 3' UTR has seven conserved sites complementary = to⁼²⁰the let-7 RNA (<= I>14),=20 a miRNA expressed in later stages of animaldevelopment = (<= I>15),=20 leading us to suspect that disrupting let-7⁼regulation=20 of Hmga2 might lead to oncogenic transformation.⁼²⁰Consistent with this idea, introducing let-7 RNA = repressed=20 Hmga2in F9 cells (Fi= g.=20 1C), an undifferentiated embryonic carcinomacell = line that=20 does not express detectable let-7 RNA (Fi= g.=20 1B).Moreover, introducing a 2'-O-methyl=20 oligonucleotide (<= I>16,=20 <= I>17)⁼²⁰complementary to let-7 RNA enhanced Hmga2 in NIH3T3 = cells (Fi= g.=20 1D),a cell line that naturally expresses = let-7 (Fi= g.=20 1B). Theseeffects were specific in that they did = not occur=20 with noncognatemiRNAs (mlet-7 and miR-101, Fi= g.=20 1C) or a noncognate inhibitor(miR-124 = 2'-O-Me, Fi= g.=20 1D).
To test whether let-7 directly targets the Hmga2 = 3' UTR,=20 weconstructed reporters with the wild-type 3' UTR = (Luc-wt)=20 andthe UTR with point mutations disrupting all seven = sites=20 (Luc-m7),the four distal sites (Luc-m4), or the two = most=20 distal sites(Luc-m2) (Fi= g.=20 2A). In F9 cells, the degree of repression corresponded⁼to=20 the number of intact sites and depended on cotransfection⁼of=20 the let-7 miRNA, whereas cotransfection of an unrelated = miRNA⁼²⁰had little effect (miR-124, Fi= g.=20 2B). The repression profileinverted when the = let-7=20 miRNA was replaced with a mutant miRNA,mlet-7 = (Fi= g.=20 2B), which was designed to recognize the mutant⁼sites=20 instead of the wild-type sites (Fi= g.=20 2A). This rescueof repression with compensatory = changes in=20 the miRNA confirmedtargeting specificity and the = importance of=20 direct pairing betweenthe sites and the miRNA.⁼

Fig. 2. Luciferase = reporter=20 assays showing the influence of miRNA-target pairing.=20 (A) Design of Luciferase constructs. The 3' UTR = of=20 murine Hmga2 was appended to the Luciferase ORF = (Luc).=20 let-7 complementary sites are indicated = (vertical red=20 lines), as are mutant sites (black Xs). The Luc-m7, = Luc-m4,=20 and Luc-m2 were identical to Luc-wt, except they had = seven,=20 four, and two mutant sites, respectively. Each mutant = site had=20 two point substitutions that disrupted pairing to = let-7=20 but created pairing to mutant let-7 = (mlet-7,=20 bottom, in blue). The seven sites were identified in a = search=20 for conserved 7- and 8-nucleotide motifs (7mer and = 8mer)=20 matching the seed region of let-7 (<= I>15).=20 (B) Reporter repression in F9 cells = supplemented with=20 the indicated miRNA. Bars are colored to indicate the = number=20 of sites mutated in the reporter. Shown are median = repression=20 values, with error bars indicating 25th and 75th = percentiles;=20 n =3D 12, except experiments with no added = miRNA (=96), in=20 which n =3D 36. Within each quartet, activity = was=20 normalized tothatofthe Luc-m7 reporter, except for the = mlet-7 quartet, for which activity was = normalized to=20 that of the Luc-m7 reporter with noncognate miRNA = (miR-124).=20 (C) Reporter repression in NIH3T3 cells (top) = or HeLa=20 cells (bottom) supplemented with the indicated miRNA,=20 performed and displayed as in (B). We also noticed two = additional let-7 complementary sites in the = murine=20 Hmga2 mRNA, but located in the 5' UTR. When = tested in=20 luciferase reporter assays, these sites mediated = little or no=20 repression in the different cell lines, and the mutant = sites=20 did not respond to mlet-7, indicating that any = effects=20 observed with the 5' UTR sites were not miRNA = specific.=20 [V= iew=20 Larger Version of this Image (45K GIF = file)]=20 =

To examine repression directed by endogenous let-7, we=20 repeatedthe reporter assays using NIH3T3 cells and = HeLa cells,=20 whichnaturally express let-7 (Fi= g.=20 1B). In both cell types, reporterrepression = depended on=20 the wild-type sites, as would be expectedif the = endogenous=20 let-7 miRNA directed repression (Fi= g.=20 2C).Adding exogenous let-7 RNA enhanced = repression,=20 suggesting thatlet-7 RNA was subsaturating in = these=20 cells. Adding mutant let-7also caused reporters = with=20 mutant sites to be repressed. Addingmlet-7 or = miR-124=20 decreased repression of the reporter withwild-type = sites=20 (particularly in HeLa cells), as if the transfected⁼miRNA was=20 competing with endogenous let-7 RNA for a limiting⁼²⁰factor.
Having established that the sites within the Hmga2 3' = UTR=20 couldmediate let-7=96directed repression, we = tested=20 whether disruptingthis repression could promote = oncogenic=20 transformation. Assaysfor anchorage-independent growth = were=20 performed with NIH3T3cells, which form colonies in = soft agar=20 when stably transfectedwith a potent oncogene. Stably=20 transfecting a vector expressingwild-type Hmga2 = did not=20 significantly increase the number ofcolonies compared = with=20 transfecting an empty vector, whereastransfecting a = vector=20 expressing a truncated Hmga2 (Hmga2-tr)(Fi= g.=20 3A), shown previously to promote anchorage-independent⁼²⁰growth (<= I>18),=20 produced significantly more colonies (Fi= g.=20 3B).As in human tumors, Hmga2-tr lacked the = spacer, the=20 acidic domain,and the entire 3' UTR with its miRNA=20 complementary sites (Fi= g.=20 3A).The increase in colonies was attributed to the = loss of=20 let-7repression rather than the truncation of = the=20 protein becausestably expressing Hmga2-m7, which had = the full=20 ORF but disruptedlet-7 complementary sites (Fi= g.=20 3A), produced at least as manycolonies as = Hmga2-tr,=20 whereas stably expressing Hmga2-ORFtr,which had the = truncated=20 ORF but intact miRNA complementary sites(Fi= g.=20 3A), produced a number comparable to that of Hmga2-wt⁼(Fi= g.=20 3B). Stably expressing Hmga2-m4, which retained the first⁼three let-7 sites, led to an intermediate number of=20 colonies.

Fig. 3. Soft-agar = assay for=20 anchorage-independent growth. (A) Hmga2 = constructs used=20 for stable transfection, depicted as in Fi= g.=20 2A. (B) Colony formation. For cells stably=20 transfected with the indicated vector, the percentage = that=20 yielded colonies after 28 days is plotted (horizontal = line,=20 median; box, 25th through 75th percentile; error bars, = range;=20 n =3D 12 from four independent experiments, = each in=20 triplicate). All but Hmga2-wt yielded a significantly = higher=20 number of colonies than did the empty vector = (Mann-Whitney=20 test for each, P < 0.05). When compared with = Hmga2-wt, a significantly higher number of colonies = was=20 observed for Hmga2-tr (P =3D 0.003). Hmga2-m7 = showed=20 significantly more colonies than any of the other = constructs=20 tested (P < 0.05 for each; *, P =3D = 0.041; **,=20 P =3D 0.002; ***, P =3D = 10⁼⁹⁶⁶). No=20 significant difference was observed between Hmga2-wt = and the=20 construct with the truncated ORF (P =3D 0.61). = [V= iew=20 Larger Version of this Image (26K GIF = file)]=20 =

We next tested whether the stably transfected cells used = to⁼²⁰assay anchorage-dependent growth were also able to form=20 subcutaneoustumors in nude mice. Consistent with our = soft-agar=20 results,tumors were observed when injecting cells = expressing=20 constructswith mutated let-7 sites: After 5 = weeks,=20 three of four miceinjected with Hmga2-m7 cells and two = of four=20 mice injected withHmga2-m4 cells had tumors at the = sites of=20 injection. One offour injected with Hmga2-tr cells and = one of=20 four injected withHmga2-ORFtr also had tumors, whereas = no=20 tumors were observed5 weeks after injecting cells = stably=20 transfected with eitherwild-type Hmga2 or empty = vector.⁼²⁰
Taken together, our results support the proposal that the=20 let-7miRNA acts as a tumor-suppressor gene (<= I>19,=20 <= I>20)=20 and indicatethat a major mechanism of oncogenic = Hmga2=20 translocations associatedwith various human tumors is = the loss=20 of let-7 repression. Thus,loss of = miRNA-directed=20 repression of an oncogene is anothertype of=20 oncogene-activating event that should be considered⁼when=20 investigating the effects of mutations associated with⁼cancer.=20 Likewise, mutations that create miRNA-directed repression⁼of=20 tumor-suppressor genes might also impart a selective = advantage⁼²⁰to the tumor cells. In this regard, we note that = Hmga2=20 translocationsfrequently append the Hmga2 3' = UTR to the=20 3' end of known tumor-suppressorgenes, including = FHIT,=20 RAD51L1, and HEI10 (5,=20 8,=20 9),=20 suggestingthat let-7=96directed repression of = these=20 translocationpartners might cooperate with disrupting=20 Hmga2 repression topromote tumorigenesis.⁼
Vertebrate miRNAs can each have hundreds of conserved = targets⁼²⁰and many additional nonconserved targets (<= I>15,=20 <= I>21=96<= I>25),⁼²⁰all of which have confounded exploration of the biological=20 impactof particular miRNA-target relationships. In = worms,=20 flies, andplants, repression of particular targets is = known to=20 be relevantbecause genetic studies have investigated = what=20 happens whenthat target alone is not repressed by the = miRNA=20 (<= I>26=96<= I>28).⁼²⁰Because of the possibility that multiple interactions = might⁼²⁰need to be perturbed to observe a phenotypic consequence = in⁼²⁰mammals, it has been unclear whether the importance of a=20 particularmammalian miRNA-target interaction can be=20 demonstrated experimentally.Our results, combined with = previous cytogenetic studies thatspeak to the effect = of=20 misregulating the endogenous human HMGA2gene, = show that=20 disrupting miRNA regulation of Hmga2 enhances⁼oncogenic=20 transformation, thereby demonstrating that disrupting⁼miRNA=20 regulation of a single mammalian gene can have a cellular⁼²⁰phenotype in vitro and a clinical phenotype in vivo.⁼

References and=20 Notes

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29. We thank M. Narita and S. Lowe for providing the Hmga2 = antibody,=20 and C. Jan, A. Grimson, and M. Narita for helpful discussions = and=20 advice. Supported by grants from the Deutsche = Forschungsgemeinschaft=20 (C.M.) and the NIH (D.B.). D.B. is a Howard Hughes Medical = Institute=20 Investigator.

Supporting Online = Material⁼²⁰
www.scien= cemag.org/cgi/content/full/1137999/DC1⁼²⁰
Materials and Methods
SOM Text
Figs. S1 and S2
References

Received for publication 27 November 2006. Accepted for = publication 13=20 February 2007.

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" + message + "

.=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_0271_01C8B117.C7A20F30 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.sciencemag.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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