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NBME 21 Answers

nbme21/Block 4/Question#4 (58.0 difficulty score)
The FOXO transcription factor responds to ...
Nuclear/cytoplasmic shuttling: yes;
Serine phosphorylation: yes
Ubiquitin-mediated proteolysis: no
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 +12 
submitted by calcium196(11),
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tbmi-iteiUqnduidea iyrosotlesp si tno leisryrbev cedtfefa by inislnu. Teh unoesiqt saks ofr rerblveise wyas taht iisnlnu ffctsae ,it adn uoiuibntnqtaii ldwou leda ot agdriontaed iva reeso,ptas hchwi is nto lrs.biervee /pcaollaNysrmcuctie uhninstg mesak seesn ubseaec OXOF is a crroatpinsint ofrt,ca so it nat’c do tis boj fi ti is in het cmpyls!ota

meningitis  Thank you for your explanation! One question: How about the serine phosphorylation? Is it answered by pure memorization that the FOXO TF is serine phosphorylated, or is it a general fact that all TF's are serine-threonine phosphorylated? +  
tsl19  I'm not sure, but it may be as simple as this: ubiquitin-mediated proteolysis is irreversible, but both N/C shuttling and phosphorylation are generally reversible processes. +  
didelphus  I also guessed that FOXO must be a part of the PI3K pathway, since insulin regulates metabolism through PI3K and the question stem specifically mentions that. Phosphorylation is a major part of that pathway, so even indirectly phosphorylation would regulate FOXO. Frustrating question. +11  
niboonsh  yes, FOXO is affected downstream of the activation of PI3K. This is a really good video that explains the whole cascade https://www.youtube.com/watch?v=ewgLd9N3s-4 +1  
alexb  According to wikipedia (https://en.wikipedia.org/wiki/FOXO1) phosphorylation of FOXO1 is irreversible. This is referring to phosphorylation of serine residues on FOXO by Akt, which occurs in response to insulin. But the NBME answer suggests it's reversible. What's up? +1  
almondbreeze  could wiki be wrong on phosphorylation being irreversible? according to this article, it is a reversible process: regulation of FoxO transcription factors by reversible phosphorylation and acetylation (https://www.sciencedirect.com/science/article/pii/S0167488911000735#s0010) some wiki info, however, is helpful : In its un-phosphorylated state, FOXO1 is localized to the nucleus, where it binds to the insulin response sequence located in the promoter for glucose 6-phosphatase and increases its rate of transcription. FOXO1, through increasing transcription of glucose-6-phosphatase, indirectly increases the rate of hepatic glucose production.[19] However, when FOXO1 is phosphorylated by Akt on Thr-24, Ser-256, and Ser-319, it is excluded from the nucleus, where it is then ubiquitinated and degraded. The phosphorylation of FOXO1 by Akt subsequently decreases the hepatic glucose production through a decrease in transcription of glucose 6-phosphatase. +  
leaf_house  It seems like the phosphorylation from Akt leads to destruction, but maybe the assumption is that that phosphorylation step (excluding every other step of ubiquitin-proteosome pathway) is reversible, where proteolysis is final. @niboonsh video is good but doesn't split this one. +  



 +7 
submitted by imgdoc(129),
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iThs noeqiust is giskna uaobt the islnnui rreeotpc noeisryt ikesan tpwaa.yh oS aket ti romf et,her

  1. The ohhroaosilpnpty fo het SRI vtaceisat a insagl utdinscronat dccaeas ttah dleas to the inttavoiac of other asinsek as lewl sa ciitoanspntrr arosfct that amieted het rnlealirctual efeftcs fo su.inlin lli/rNocameytscpuaC utghsiltn - sey iv)el(rreebs

  2. nreeioShTninre/e aknsise are loas nwkon to uredce teh vittiacy fo ni.uilsn - sye bsrei)vel(re

  3. iquiUbtin - emdditea ptysrlioeos - on nto( sve)belirre, nad loas inunsil itoaeyclmblal sraiences teproin nisystseh so ti 'odnest acthm atwh unlinis edos s.yawyan

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usmle11a  i think youre correct cause ubiquitin mediated proteolyis is an irreversible step. +1  



 +4 
submitted by hello(257),
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heT Q tsem tseats FXOO is a insiptarrntoc taforc tath onpsdrse to nuiisln gnlgasini yb garteiln hte tpsnitonraicr of claotembi esneg -&-;gt ,heertfoer OFXO is a tnricoasitrpn fatroc voldneiv in ltebosmai.m hisT oludsh aekm ssene seabcue psticnirn-uorele natoivatci sah a orle ni nuegrgitla e.sloimmbta

ihsT Q sksa aobtu lrbeesrvei syaw htat lniuisn gesaetru XOOF scpratinonrt arocft iy.vticta

qbUinduia-medettii tposlesiyro is leerrbirseiv. tnaieElmi lal cesohic tcxeep fro ,B D, dan H.

iroetIsupre-nnslc cuonftin hougrth I3PK linggis.an I3KP nnggsiila isneolvv tpplooioyhrhsan of senrie tg-;-& esneri solrthhiyoppona is a bilerevrse prosc.es Etalnmiei .H IFY: ateniorpin/om acdi horpopiatlynhos is walsay eesevibrl.r

oYu ear felt twhi hcosice B nad D.

FOOX is a srcttinnairpo aotfrc t;-g-& nrritoiantscp rsacotf mtdeeia egne ivayittc yb isttnuhlg beeentw eht scplyatom and slcnu.ue gniulRtgea teh otinacol fo OOXF sprrtioaictnn aofcrt i.(e. asoypclmt .vs e)lnucus lwil hrortefee brslerievy aodmulte OmtOae-ddFeXi mctboelia eeng viity.act

shiT seavle uyo iwth the roerctc sarwn:e heoicC .B

adong  A better way to think about it is insulin acts through MAPK which is a serine/threonine kinase +  



 +1 
submitted by usmleuser007(335),
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reinSe pprthiynaosholo illw deeruc inslns'iu etasfc.f It asct on eth sonietyr aineks.