Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS One. 2010 Apr 29;5(4):e10409. doi: 10.1371/journal.pone.0010409.
Beclin 1 plays an essential role in autophagy; however, the regulation of Beclin 1 expression remains largely unexplored. An earlier ChIP-on-chip study suggested Beclin 1 could be an E2F target. Previously, we also reported that 14-3-3tau regulates E2F1 stability, and is required for the expression of several E2F1 target genes. 14-3-3 proteins mediate many cellular signaling processes, but its role in autophagy has not been investigated. We hypothesize that 14-3-3tau could regulate Beclin 1 expression through E2F1 and thus regulate autophagy.
Using the RNAi technique we demonstrate a novel role for one of 14-3-3 isoforms, 14-3-3tau, in the regulation of Beclin 1 expression and autophagy. Depletion of 14-3-3tau inhibits the expression of Beclin 1 in many different cell lines; whereas, upregulation of 14-3-3tau induces Beclin 1. The regulation is physiologically relevant as an extracellular matrix protein tenascin-C, a known 14-3-3tau inducer, can induce Beclin 1 through 14-3-3tau. Moreover, rapamycin-induced, serum free-induced and amino acid starvation-induced autophagy depends on 14-3-3tau. We also show the expression of Beclin 1 depends on E2F, and E2F can transactivate the Beclin 1 promoter in a promoter reporter assay. Upregulation of Beclin 1 by 14-3-3tau requires E2F1. Depletion of E2F1, like 14-3-3tau, also inhibits autophagy.
Taken together, this study uncovers a role for 14-3-3tau in Beclin 1 and autophagy regulation probably through regulation of E2F1.
Beclin 1 在自噬中起着至关重要的作用；然而，Beclin 1 表达的调控在很大程度上仍未得到探索。早期的 ChIP-on-chip 研究表明 Beclin 1 可能是 E2F 的靶标。此前，我们还报告称 14-3-3tau 调节 E2F1 的稳定性，是几个 E2F1 靶基因表达所必需的。14-3-3 蛋白介导许多细胞信号转导过程，但它在自噬中的作用尚未得到研究。我们假设 14-3-3tau 可以通过 E2F1 调节 Beclin 1 的表达，从而调节自噬。
使用 RNAi 技术，我们证明了 14-3-3 同工型之一 14-3-3tau 在调节 Beclin 1 表达和自噬中的新作用。在许多不同的细胞系中，14-3-3tau 的耗竭抑制了 Beclin 1 的表达；而 14-3-3tau 的上调诱导了 Beclin 1。这种调控具有生理相关性，因为细胞外基质蛋白 tenascin-C 是已知的 14-3-3tau 诱导剂，它可以通过 14-3-3tau 诱导 Beclin 1。此外，雷帕霉素诱导的、无血清诱导的和氨基酸饥饿诱导的自噬依赖于 14-3-3tau。我们还表明，Beclin 1 的表达依赖于 E2F，并且 E2F 可以在启动子报告基因测定中通过 E2F 转激活 Beclin 1 启动子。14-3-3tau 上调 Beclin 1 需要 E2F1。E2F1 的耗竭，就像 14-3-3tau 一样，也抑制了自噬。
综上所述，这项研究揭示了 14-3-3tau 在 Beclin 1 和自噬调控中的作用，可能是通过调节 E2F1 实现的。
