Crosstalk between c-Jun and TAp73alpha/beta contributes to the apoptosis-survival balance.
Crosstalk between c-Jun and TAp73alpha/beta contributes to the apoptosis-survival balance.
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DOI：
10.1093/nar/gkr028
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发表时间：
2011-08
影响因子：
14.9
通讯作者：
Lohrum M
中科院分区：
文献类型：
--
作者：
Koeppel M;van Heeringen SJ;Kramer D;Smeenk L;Janssen-Megens E;Hartmann M;Stunnenberg HG;Lohrum M
P53家族成员p73在发育和生长控制的各种细胞信号通路中发挥作用，并具有肿瘤抑制特性。P73的几种亚型在功能上有很大的不同。尽管N端异构体(TA和TAp73)的功能及其相反的促凋亡和抗凋亡作用已变得明显，但Δ73不同的C端剪接形式的功能差异仍不清楚。在这里，我们用染色质免疫沉淀测序鉴定了TAp73RNA和TAp73RNA的全球基因组结合位点，并通过测序分析了转录反应。我们鉴定了一个特定的p73共识结合基序，并在TAp73α的结合位点附近发现了强烈的AP1基序。这些含有AP1基序的靶基因被TAp73α选择性地上调，而它们的基因表达在TAp73β诱导下被抑制。我们发现它们的表达依赖于内源性的c-jun，并且c-jun的募集到相应的AP1部位受到TAp73β表达的影响，部分原因是c-jun的下调。其中一些含有TAp73α诱导基因的AP1位点参与了细胞凋亡的诱导，提示了TAp73α和TAp73β功能差异的分子机制。
The p53-family member p73 plays a role in various cellular signaling pathways during development and growth control and it can have tumor suppressor properties. Several isoforms of p73 exist with considerable differences in their function. Whereas the functions of the N-terminal isoforms (TA and ΔNp73) and their opposing pro- and antiapoptotic roles have become evident, the functional differences of the distinct C-terminal splice forms of TAp73 have remained unclear. Here, we characterized the global genomic binding sites for TAp73α and TAp73β by chromatin immunoprecipitation sequencing as well as the transcriptional responses by performing RNA sequencing. We identified a specific p73 consensus binding motif and found a strong enrichment of AP1 motifs in close proximity to binding sites for TAp73α. These AP1 motif-containing target genes are selectively upregulated by TAp73α, while their mRNA expression is repressed upon TAp73β induction. We show that their expression is dependent on endogenous c-Jun and that recruitment of c-Jun to the respective AP1 sites was impaired upon TAp73β expression, in part due to downregulation of c-Jun. Several of these AP1-site containing TAp73α-induced genes impinge on apoptosis induction, suggesting an underlying molecular mechanism for the observed functional differences between TAp73α and TAp73β.