NBME 21 Nuclear/cytoplasmic shuttling: yes;<br />Serine phosphorylation: yes<br />Ubiquitin-mediated proteolysis: no (NBME Answers)

Retired NBME 21 Answers

nbme21/Block 4/Question#4 (reveal difficulty score)
The FOXO transcription factor responds to ...
Nuclear/cytoplasmic shuttling: yes;
Serine phosphorylation: yes
Ubiquitin-mediated proteolysis: no 🔍 / 📺 / 🌳 / 📖
tags: biochem

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submitted by calcium196(12)

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Ubiquitin-mediated proteolysis is not reversibly affected by insulin. The question asks for reversible ways that insulin affects it, and ubiquitination would lead to degradation via proteases, which is not reversible. Nuclear/cytoplasmic shunting makes sense because FOXO is a transcription factor, so it can’t do its job if it is in the cytoplasm!

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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. +21

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 +2

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? +2

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. +

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submitted by ∗imgdoc(183)

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This question is asking about the insulin receptor tyrosine kinase pathway. So take it from there,

The phosphorylation of the IRS activates a signal transduction cascade that leads to the activation of other kinases as well as transcription factors that mediate the intracellular effects of insulin. Nuclear/Cytoplasmic shuttling - yes (reversible)
Serine/Threonine kinases are also known to reduce the activity of insulin. - yes (reversible)
Ubiquitin - mediated proteolysis - no (not reversible), and also insulin metabolically increases protein synthesis so it doesn't match what insulin does anyways.

correct me if I'm wrong.

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

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submitted by ∗hello(429)

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The Q stem states FOXO is a transcription factor that responds to insulin signaling by altering the transcription of metabolic genes --> therefore, FOXO is a transcription factor involved in metabolism. This should make sense because insulin-receptor activation has a role in regulating metabolism.

This Q asks about reversible ways that insulin reguates FOXO transcrption factor activity.

Ubiquitin-mediated proteolysis is irreversible. Eliminate all choices except for B, D, and H.

Insulin-receptors function through PI3K signaling. PI3K signaling involves phosphorylation of serine --> serine phosphorylation is a reversible process. Eliminate H. FYI: protein/amino acid phosphorylation is always reversible.

You are left with choices B and D.

FOXO is a transcription factor --> transcription factors mediate gene activity by shuttling between the cytoplasm and nucleus. Regulating the location of FOXO transcription factor (i.e. cytoplasm vs. nucleus) will therefore reversibly modulate FOXO-mediated metabolic gene activity.

This leaves you with the correct answer: Choice B.

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adong A better way to think about it is insulin acts through MAPK which is a serine/threonine kinase +1

amy I intepretated Nuclear/Cytoplasmic shuttling would be the result of serine phosphorylation, so the reversible modification is only on serine phosphorylation, which lead to nuclear/cytoplasmic shuttling, but the shuttling itself is not under modification. I got it wrong. +

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submitted by ∗usmleuser007(464)

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Serine phosphorylation will reduce insulin's affects. It acts on teh tyrosine kinase.

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alexandramda https://www.cell.com/current-biology/pdf/S0960-9822(07)00809-3.pdf +

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