Sirt1, pancreas cells and insulin signals

[Guest guest]

Hi All,

The roles in health and longevity of Sir proteins, CR and insulin signals have

been

studied (1-3).

A new report (4) on a not pdf-available article (5) associating Sirt1 and

insulin

signaling are below.

It seems that Sirt1 goes to the cells of the organ that generates insulin for

the

body, the pancreas. In vivo studies may have been of greater interest.

Further,

(4) provides ample introduction to (5).

1: Gan L, Han Y, Bastianetto S, Dumont Y, Unterman TG, Quirion R.

FoxO-dependent and -independent mechanisms mediate SirT1 effects on IGFBP-1

gene expression.

Biochem Biophys Res Commun. 2005 Dec 2;337(4):1092-6. Epub 2005 Oct 5.

PMID: 16236254

2: BJ.

A forkhead in the road to longevity: the molecular basis of lifespan becomes

clearer.

J Hypertens. 2005 Jul;23(7):1285-309.

PMID: 15942449

3: Al-Regaiey KA, Masternak MM, Bonkowski M, Sun L, Bartke A.

Long-lived growth hormone receptor knockout mice: interaction of reduced

insulin-like growth factor i/insulin signaling and caloric restriction.

Endocrinology. 2005 Feb;146(2):851-60. Epub 2004 Oct 21.

PMID: 15498882

(4) [No authors listed]

Research Highlights.

Nat Genet. 2005 Nov;37(11):1169. No abstract available.

PMID: 16254561

Alan Packer

Stress and the beta cell

The forkhead transcription factor FoxO1 is a key regulator of pancreatic beta

cell

mass. Yukari Ido Kitamura and colleagues now show that it also protects against

beta

cell failure in response to acute oxidative stress (Cell Metab. 2, 153–163;

2005).

FoxO1 typically shuttles between the nucleus and cytoplasm, but the authors show

that incubation of beta cells with hydrogen peroxide induces predominantly

nuclear

localization. This redistribution is accompanied by the direct activation of

NeuroD

and MafA, two transcription factors that regulate insulin II gene expression.

They

also observed interaction of FoxO1 with nuclear Pml bodies, which targets FoxO1

for

ubiquitin-mediated degradation. These data are tied together in a model for

regulation of FoxO1. In response to hyperglycemia or oxidative stress, FoxO1 is

acetylated and localized to Pml bodies. This blocks both ubiquitination of FoxO1

and

its transcriptional activity. Association with Pml bodies then results in

deacetylation of FoxO1 by Sirt1, leading to FoxO1-dependent transcription and

rapid

degradation of FoxO1. The authors propose that this mechanism may allow for the

protection of beta cells against acute stress but not against the chronic

effects of

prolonged hyperglycemia, itself a cause of oxidative stress. AP

(5) Kitamura YI, Kitamura T, Kruse JP, Raum JC, Stein R, Gu W, Accili D.

FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA

induction.

Cell Metab. 2005 Sep;2(3):153-63.

PMID: 16154098

Diabetes causes pancreatic beta cell failure through hyperglycemia-induced

oxidative

stress, or " glucose toxicity. " We show that the forkhead protein FoxO1 protects

beta

cells against oxidative stress by forming a complex with the promyelocytic

leukemia

protein Pml and the NAD-dependent deacetylase Sirt1 to activate expression of

NeuroD

and MafA, two Insulin2 (Ins2) gene transcription factors. Using

acetylation-defective and acetylation-mimicking mutants, we demonstrate that

acetylation targets FoxO1 to Pml and prevents ubiquitin-dependent degradation.

We

show that hyperglycemia suppresses MafA expression in vivo and that MafA

inhibition

can be prevented by transgenic expression of constitutively nuclear FoxO1 in

beta

cells. The findings provide a mechanism linking glucose- and growth factor

receptor-activated pathways to protect beta cells against oxidative damage via

FoxO

proteins.

Al Pater, PhD; email: old542000@...

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