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NBME 21 Answers

nbme21/Block 4/Question#4

The FOXO transcription factor responds to insulin ...

Nuclear/cytoplasmic shuttling: yes;
Serine phosphorylation: yes
Ubiquitin-mediated proteolysis: no

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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!

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. +5  
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 +  
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  upvote downvote
submitted by imgdoc(33),

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

  1. 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)

  2. Serine/Threonine kinases are also known to reduce the activity of insulin. - yes (reversible)

  3. 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.

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

 +2  upvote downvote
submitted by hello(80),

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.

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