From: Subject: Molecular Cell -- Liu et al. Date: Wed, 17 May 2006 14:05:58 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C679BB.054808D0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C679BB.054808D0 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.molecule.org/content/article/abstract?uid=PIIS1097276506000116 =EF=BB=BF Molecular Cell -- Liu et = al.

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Article

Hypoxia-Induced Energy = Stress=20 Regulates mRNA Translation and Cell Growth

Liping Liu,^¹,²=20Timothy=20 P. Cash,^²=20Russell=20 G. Jones,^²=20Brian Keith,^²=20Craig=20 B. Thompson,^²=20and M.=20 Celeste Simon^¹,²,

1 Howard Hughes=20 Medical Institute, University of Pennsylvania School of Medicine, = 421=20 Curie Boulevard, Philadelphia, Pennsylvania 191042 Abramson Family=20 Cancer Research Institute, University of Pennsylvania School of = Medicine,=20 421 Curie Boulevard, Philadelphia, Pennsylvania 19104

Correspondence:
M. Celeste Simon
Ph: (215) = 746-5532;=20 Fax: (215) 746-5511
celeste2@mail.med.upenn.edu

Article Options
= Table=20 of Contents Full=20 Text PDF=20 (679K) Supplemen= tal=20 Data
Search Medline = for
Liping= =20 Liu M. = Celeste Simon
Related = Articles
TOR=20 Signaling in Growth and Metabolism... TSC2=20 Mediates Cellular Energy Response to Control ... Phosphorylation=20 and Functional Inactivation of TSC... More=20 related=20 articles...

Summary
Oxygen (O₂) deprivation, = or=20 hypoxia, has profound effects on cell metabolism and growth. Cells = can=20 adapt to low O₂ in part through activation of = hypoxia-inducible=20 factor (HIF). We report here that hypoxia inhibits mRNA = translation by=20 suppressing multiple key regulators, including eIF2=CE=B1, eEF2, = and the=20 mammalian target of rapamycin (mTOR) effectors 4EBP1, = p70^S6K,=20 and rpS6, independent of HIF. Hypoxia results in energy starvation = and=20 activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic = AMP-activated=20 protein kinase (AMPK) activation also leads to eEF2 inhibition. = Moreover,=20 hypoxic effects on cellular bioenergetics and mTOR inhibition = increase=20 over time. Mutation of the TSC2 tumor suppressor gene confers a = growth=20 advantage to cells by repressing hypoxic mTOR inhibition and=20 hypoxia-induced G₁ arrest. Together, eIF2=CE=B1, eEF2, = and mTOR=20 inhibition represent important HIF-independent mechanisms of = energy=20 conservation that promote survival under low O₂=20 conditions.

Cell		Immunity		Neuron		Molecular Cell		Structure
Current=20 Biology		Developmental = Cell		Cancer = Cell		Chemistry &=20 Biology		Cell=20 Metabolism

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http://www.molecule.org/webfiles/javascript/script.js function dropdown(list) { var item=3Dlist.options[list.selectedIndex].value; if (item !=3D "nowhere")=20 { top.location=3Ditem; } } =09 function openhelp() { window.open('/popup/help', 'helpwindow', = 'width=3D580,height=3D410,left=3D0,top=3D0,screenX=3D0,screenY=3D0,resiza= ble=3Dno,scrollbars=3Dyes'); self.name=3D"main"; } function opensearchhelp() { = window.open('/popup/help/Finding_Information.htm','helpwindow','width=3D5= 80,height=3D410,left=3D0,top=3D0,screenX=3D0,screenY=3D0,resizable=3Dno,s= crollbars=3Dyes'); self.name=3D"main"; } function statecodeselect(thisform, thislist, list1, list2, = countrycodefield, countrydescfield) { var theform =3D eval("document." + thisform); var thelist =3D eval("theform." + thislist); eval("theform." + list1 + ".selectedIndex=3D0"); eval("theform." + list2 + ".selectedIndex=3D0"); eval("theform.elements[\"" + countrycodefield + = "\"].value=3Dthelist.options[thelist.selectedIndex].text"); eval("theform.elements[\"" + countrydescfield + = "\"].value=3Dthelist.options[thelist.selectedIndex].text"); } function clearstates ( thisform, strControlNameRoot, strIdentifiers ) { eval ( "document." + thisform + "." + strControlNameRoot + = ".value=3D''" ); var colIdentifiers =3D strIdentifiers.split ( ";" ); for ( var iCounter =3D 0; iCounter < colIdentifiers.length; iCounter++ = ) eval ( "document." + thisform + "." + strControlNameRoot + "_" + = colIdentifiers[iCounter] + ".selectedIndex=3D0" ); } function finalstate ( thisform, strControlNameRoot, strSelectRef, = strIdentifiers ) { var strCountryID =3D eval ( "document." + thisform + "." + strSelectRef = + ".options[document." + thisform + "." + strSelectRef + = ".selectedIndex].value" ); if ( strIdentifiers.indexOf ( strCountryID ) =3D=3D -1 || strCountryID = =3D=3D "0") return; var strStateID =3D eval ( "document." + thisform + "." + = strControlNameRoot + "_" + strCountryID + ".options[document." + = thisform + "." + strControlNameRoot + "_" + strCountryID + = ".selectedIndex].value" ); eval ( "document." + thisform + "." + strControlNameRoot ).value =3D = strStateID; } function setstate ( thisform, strControlNameRoot, strIdentifier, = strSelectRef, strIdentifiers, evt ) { // The following line ensures that the event type can be picked up = across all IE and NN var eventType =3D evt.type || arguments.callee.caller.name || = window.event.type; if ( eventType.indexOf ( "on" ) !=3D 0 ) eventType =3D "on" + eventType; if ( strIdentifier !=3D "" ) { if ( eval ( "document." + thisform + "." + strSelectRef + = ".options[document." + thisform + "." + strSelectRef + = ".selectedIndex].value" ) !=3D strIdentifier ) { // This part will be hit if the user selects a drop down that isn't = the one that they should // The country has not been set, or is set to something other than = the state box that was selected // Need to do two things. Set the country to the relevant value and = clear the other boxes if ( eventType =3D=3D "onchange" ) { // First, clear the other drop downs' values var colIdentifiers =3D strIdentifiers.split ( ";" ); for ( var iCounter =3D 0; iCounter < colIdentifiers.length; = iCounter++ ) { if ( colIdentifiers[iCounter] !=3D strIdentifier ) eval ( "document." + thisform + "." + strControlNameRoot + "_" + = colIdentifiers[iCounter] + ".selectedIndex=3D0" ); } // Clear the text box eval ( "document." + thisform + "." + strControlNameRoot + = ".value=3D''" ); // Now set the country eval ( "document." + thisform + "." + strSelectRef + ".selectedIndex = =3D " + searchArray ( eval ( "document." + thisform + "." + strSelectRef = + ".options" ), strIdentifier ) ); } return; } return; } else { if ( ( eval ( "document." + thisform + "." + strSelectRef + = ".selectedIndex" ) =3D=3D 0 ) || ( eval ( "document." + thisform + "." + strSelectRef + = ".options[document." + thisform + "." + strSelectRef + = ".selectedIndex].value" ) =3D=3D 1224 ) || ( eval ( "document." + thisform + "." + strSelectRef + = ".options[document." + thisform + "." + strSelectRef + = ".selectedIndex].value" ) =3D=3D 1037 ) ) { // This part will be entered when the user selects the text box and = that doesn't match what's in the country box // What needs to be done is the country box is aligned and the other = state input boxes to be reset if ( eventType =3D=3D "onchange" ) { // First, clear the drop downs' values var colIdentifiers =3D strIdentifiers.split ( ";" ); for ( var iCounter =3D 0; iCounter < colIdentifiers.length; = iCounter++ ) eval ( "document." + thisform + "." + strControlNameRoot + "_" + = colIdentifiers[iCounter] + ".selectedIndex=3D0" ); // Now set the country // Should we set it to a country? Or should it be blank? Think it = should be set to blank. eval ( "document." + thisform + "." + strSelectRef + ".selectedIndex = =3D 0" ); } return; } return; } } // This function searches an array and returns the index at which the = search string occurs function searchArray ( arrToSearch, strSearchValue ) { for ( var iCounter =3D 0; iCounter < arrToSearch.length; iCounter++ ) if ( arrToSearch[iCounter].value =3D=3D strSearchValue ) return iCounter; return -1; } function sethidden(value,field,value2) { if(!value2) { if(field.options) value2=3Dfield.options[field.selectedIndex].value; else value2=3Dfield.value; } if(value2!=3D"") { field.form.elements[value].value=3Dvalue2; } } function setEcommerce2Hidden() { sethidden('titleid',orderdetails.addresstitleid); sethidden('firstname',orderdetails.addressfirstname); sethidden('lastname',orderdetails.addresslastname); sethidden('address1',orderdetails.addressstreet); sethidden('address2',orderdetails.addressstreet2); sethidden('city',orderdetails.addresscity); sethidden('state',orderdetails.addressstate); sethidden('countryid',orderdetails.addresscountry); sethidden('zip',orderdetails.addresspostcode); sethidden('telephone',orderdetails.addressphone); } // Logic for YOAS checkboxs function yoasValidate(ckb) { var cnt =3D document.journals.journal.length - 3; var bk =3D document.journals.backfile.length >=3D 3; =09 if (bk) { //alert("records " + cnt); for (j =3D cnt; j < (cnt+3); j++)=20 { if (eval("document.journals.journal[" + (j) + "].checked") =3D=3D = true)=20 { document.journals.journal[j].checked =3D false; if (j - cnt =3D=3D ckb - 1)=20 { document.journals.journal[j].checked =3D true; } } } } } function noCheckbox() { for (j =3D 0; j < checkbox_form.uid.length; j++) { =20 if (checkbox_form.uid[j].checked) {=20 return true;=20 } =20 } msg =3D "Please select at least one checkbox"; alert(msg); return (false); } function encode(string){ =20 return string; } ------=_NextPart_000_0000_01C679BB.054808D0--

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Hypoxia-Induced Energy = Stress=20 Regulates mRNA Translation and Cell Growth

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Liping Liu,^¹,²=20Timothy=20 P. Cash,^²=20Russell=20 G. Jones,^²=20Brian Keith,^²=20Craig=20 B. Thompson,^²=20and M.=20 Celeste Simon^¹,²,