Fatty Acid-binding Protein 5 and PPARβ/δ Are Critical Mediators of Epidermal Growth Factor Receptor-induced Carcinoma Cell Growth
Fatty Acid-binding Protein 5 and PPARβ/δ Are Critical Mediators of Epidermal Growth Factor Receptor-induced Carcinoma Cell Growth
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DOI：
10.1074/jbc.m109.099770
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发表时间：
2010-06-18
影响因子：
4.8
通讯作者：
Noy, Noa
中科院分区：
文献类型：
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作者：
Kannan-Thulasiraman, Padmamalini;Seachrist, Darcie D.;Noy, Noa
表皮生长因子及其受体（EGFRs）促进乳腺癌细胞增殖并驱动肿瘤发生。然而，介导这些作用的分子机制尚不完全清楚。我们之前的研究表明，乳腺癌小鼠模型MMTV-neu（以乳腺组织中EGFR ErbB2扩增为特征的模型）的乳腺肿瘤发展与脂肪酸结合蛋白5 （FABP5）的显著上调相关。FABP5的功能是向核受体过氧化物酶体增殖体激活受体β / δ (PPAR β / δ)传递配体并增强其转录活性，PPAR β / δ是一种靶基因包括参与细胞生长和存活的基因的受体。我们发现在MCF-7乳腺癌细胞中，EGFR信号直接上调FABP5的表达。数据表明，EGFR配体heregulin- β 1信号通过ERK和磷脂酰肌醇-3激酶级联处理这些细胞，导致转录因子NF-kappa B的激活。反过来，NF-kappa B通过该基因启动子中的两个同源应答元件诱导FABP5的表达。观察结果进一步表明，FABP5和PPAR β / δ是EGFR增强细胞增殖能力的关键介质，表明该转录途径在EGFR诱导的肿瘤发生中起关键作用。进一步的观察表明，FABP5的表达被kruppel样因子KLF2下调，表明该因子具有肿瘤抑制活性。
Epidermal growth factors and their receptors (EGFRs) promote breast cancer cell proliferation and can drive tumorigenesis. However, the molecular mechanisms that mediate these effects are incompletely understood. We previously showed that mammary tumor development in the mouse model of breast cancer MMTV-neu, a model characterized by amplification of the EGFR ErbB2 in mammary tissue, correlates with a marked up-regulation of fatty acid-binding protein 5 (FABP5). FABP5 functions to deliver ligands to and enhance the transcriptional activity of the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta), a receptor whose target genes include genes involved in cell growth and survival. We show here that in MCF-7 mammary carcinoma cells, EGFR signaling directly up-regulates the expression of FABP5. The data demonstrate that treatment of these cells with the EGFR ligand heregulin-beta 1 signals through the ERK and the phophatidylinositol-3-kinase cascades, resulting in activation of the transcription factor NF-kappa B. In turn, NF-kappa B induces the expression of FABP5 through two cognate response elements in the promoter of this gene. The observations further demonstrate that FABP5 and PPAR beta/delta are critical mediators of the ability of EGFR to enhance cell proliferation, indicating that this transcriptional pathway plays a key role in EGFR-induced tumorigenesis. Additional observations indicate that the expression of FABP5 is down-regulated by the Kruppel-like factor KLF2, suggesting a tumor suppressor activity for this factor.