PITX2 isoform-specific regulation of atrial natriuretic factor expression - Synergism and repression with Nkx2.5
PITX2 isoform-specific regulation of atrial natriuretic factor expression - Synergism and repression with Nkx2.5
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DOI：
10.1074/jbc.m210163200
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发表时间：
2003-06-20
影响因子：
4.8
通讯作者：
Amendt, BA
中科院分区：
文献类型：
--
作者：
Ganga, M;Espinoza, HM;Amendt, BA
PITX 2和Nkx2.5是脊椎动物心脏发育的两个最早已知的转录标记。Pitx 2（-/-）小鼠存在严重的心脏畸形和胚胎致死性，证明了PITX 2在心脏发育中的作用。然而，对PITX 2在心脏发生中的下游靶点知之甚少。我们在这里报告，心房利钠因子（ANF）启动子是PITX 2的目标。PITX 2A、PITX 2B和PITX 2C同种型差异性地激活ANF启动子。然而，在Nkx2.5存在下，只有PITX 2C可以协同激活ANF启动子。我们进一步证明，前胶原赖氨酰羟化酶（PLOD 1）启动子受Nkx2.5。机制上，PITX 2C和Nkx2.5通过结合到它们各自的DNA元件协同调节ANF和PLOD 1表达。令人惊讶的是，ANF和PLOD 1启动子的PITX 2A活化被C3 H10 T1/ 2胚胎成纤维细胞系中Nkx2.5的共转染所抑制。Pitx 2a和Pitx 2c在C3 H10 T1/ 2细胞中内源性表达，并且这些细胞表达差异调节PITX 2同种型活性的因子。我们提供了一个新的机制，通过调节ANF和PLOD 1基因表达和Nkx2.5转录活性的PITX 2亚型的心脏发育的调节。
PITX2 and Nkx2.5 are two of the earliest known transcriptional markers of vertebrate heart development. Pitx2(-/-) mice present with severe cardiac malformations and embryonic lethality, demonstrating a role for PITX2 in heart development. However, little is known about the downstream targets of PITX2 in cardiogenesis. We report here that the atrial natriuretic factor ( ANF) promoter is a target of PITX2. PITX2A, PITX2B, and PITX2C isoforms differentially activate the ANF promoter. However, only PITX2C can synergistically activate the ANF promoter in the presence of Nkx2.5. We further demonstrate that the procollagen lysyl hydroxylase ( PLOD1) promoter is regulated by Nkx2.5. Mechanistically, PITX2C and Nkx2.5 synergistically regulate ANF and PLOD1 expression through binding to their respective DNA elements. Surprisingly, PITX2A activation of the ANF and PLOD1 promoters is repressed by co- transfection of Nkx2.5 in the C3H10T1/ 2 embryonic fibroblast cell line. Pitx2a and Pitx2c are endogenously expressed in C3H10T1/ 2 cells, and these cells express factors that differentially regulate PITX2 isoform activities. We provide a new mechanism for the regulation of heart development by PITX2 isoforms through the regulation of ANF and PLOD1 gene expression and Nkx2.5 transcriptional activity.