SIRT1 Promotes Differentiation of Normal Human Keratinocytes
SIRT1 Promotes Differentiation of Normal Human Keratinocytes
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DOI：
10.1038/jid.2008.179
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发表时间：
2009-01-01
影响因子：
6.5
通讯作者：
Loureiro, Joseph Jorge
中科院分区：
文献类型：
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作者：
Blander, Gil;Bhimavarapu, Anupama;Loureiro, Joseph Jorge
Sir2调节模式生物的寿命，这激发了人们对了解人类Sir2同源功能的兴趣。人类Sir2基因家族包括七个成员（SIRT1-SIRT7）。SIRT1是一种依赖于烟酰胺腺嘌呤二核苷酸（NAD(+)）的去乙酰化酶，其酶性质与酵母酶没有区别。我们通过转录微阵列分析过表达或过表达SIRT1的原代角质形成细胞，研究了SIRT1在正常人类角质形成细胞生理学中的作用。使用系统生物学分析方法，我们预测SIRT1通过与钙诱导分化完整或重叠的途径诱导角化细胞分化。我们通过实验分析了这一预测，发现SIRT1抑制剂烟酰胺抑制角质细胞分化标志物的表达，而SIRT1激活剂白藜芦醇则增强角质细胞分化标志物的表达。在过表达或过表达SIRT1的角质形成细胞中也得到了类似的结果，SIRT1的调节显著影响了角质形成细胞的增殖率。我们得出结论，SIRT1在正常人角质形成细胞中起抑制增殖和促进分化的作用。
Sir2 regulates lifespan in model organisms, which has stimulated interest in understanding human Sir2 homolog functions. The human Sir2 gene family comprises seven members (SIRT1-SIRT7). SIRT1, the human ortholog of the yeast Sir2 by closest sequence similarity, is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase with enzymatic properties indistinguishable from the yeast enzyme. We studied the involvement of SIRT1 in normal human keratinocyte physiology by a transcriptional microarray analysis of primary keratinocytes either overexpressing or underexpressing SIRT1. Using a systems biology analytical approach, we predicted that SIRT1 induces keratinocyte differentiation through a pathway integral to or overlapping with that of calcium-induced differentiation. We experimentally assayed this prediction and found that the SIRT1 inhibitor nicotinamide inhibited expression of keratinocyte differentiation markers, whereas a SIRT1 activator, resveratrol, enhanced expression of keratinocyte differentiation markers. Similar results were obtained in keratinocytes manipulated to overexpress or underexpress SIRT1, and modulating SIRT1 significantly affected keratinocyte proliferation rates. We conclude that SIRT1 functions in normal human keratinocytes to inhibit proliferation and to promote differentiation.