Regulation of the p53 homolog p73 by adenoviral oncogene E1A
Regulation of the p53 homolog p73 by adenoviral oncogene E1A
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DOI：
10.1074/jbc.m211704200
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发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Somasundaram, K
中科院分区：
文献类型：
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作者：
Das, S;El-Deiry, WS;Somasundaram, K
p73是p53同系物，因为它们在结构和功能上相似。与p53不同，p73不会被病毒致癌基因如SV 40 T抗原和人乳头瘤病毒E6的产物灭活。在这里，我们表明，腺病毒癌基因E1 A的产物抑制p73 α和p73 β的转录激活。电泳迁移率变动分析表明，E1 A不抑制p73的序列特异性DNA结合。野生型（WT）E1 A，但不是由N-末端缺失突变体E1 A（Delta 2 -36）抑制的转录激活的融合蛋白含有Gal 4 DNA结合结构域和p73的激活结构域。E1 A（Delta 2 -36）不结合p300/CBP家族的共激活因子，不能抑制p73介导的转录，而E1 A（DeltaCR 2），一种不结合pRb家族蛋白的缺失突变体，与WT E1 A一样有效地抑制p73介导的转录。与这些观察结果一致，WT E1 A消除了由重组腺病毒表达的p73诱导的生长停滞，这与E1 A抑制p73介导的p21诱导（WAF 1/CIP 1）相关。然而，p73能够诱导p21（WAF 1/CIP 1）并在E1 A（Delta 2 -36）存在下介导生长停滞。此外，野生型E1 A或E1 A（Δ 2 -36）的表达导致内源性p73的稳定。然而，响应于E1 A（Delta 2 -36）的表达而稳定的p73（而非WT E1 A）能够激活p21（WAF 1/CIP 1）的表达。这些结果表明，转录激活功能的p73是专门针对E1 A通过一种机制，涉及p300/CBP蛋白在转化过程中，p73可能有一个角色，发挥作为一个肿瘤抑制因子。
p73 is a p53 homolog, as they are similar structurally and functionally. Unlike p53, p73 is not inactivated by the products of viral oncogenes such as SV40 T antigen and human papilloma virus E6. Here we show that the product of adenoviral oncogene E1A inhibits the transcriptional activation by both p73alpha and p73beta. Electrophoretic mobility shift assays revealed that E1A does not inhibit the sequence-specific DNA binding by p73. Transcriptional activation by a fusion protein containing the Gal4 DNA-binding domain and either of the activation domains of p73 was inhibited by wild-type (WT) E1A, but not by the N-terminal deletion mutant E1A(Delta2-36). E1A(Delta2-36), which does not bind to the p300/CBP family of coactivators, failed to inhibit p73-mediated transcription, whereas E1A(DeltaCR2), a deletion mutant that does not bind to the pRb family of proteins, inhibited p73-mediated transcription as efficiently as WT E1A. Consistent with these observations, growth arrest induced by p73 expressed from a recombinant adenovirus was abrogated by WT E1A, which correlated with inhibition of p73-mediated induction of p21(WAF1/CIP1) by E1A. However, p73 was able to induce p21(WAF1/CIP1) and to mediate growth arrest in the presence of E1A(Delta2-36). Furthermore, the expression of either wild-type E1A or E1A(Delta2-36) resulted in the stabilization of endogenous p73. However, p73 stabilized in response to the expression of E1A(Delta2-36), but not WT E1A, was able to activate the expression of p21(WAF1/CIP1). These results suggest that the transcriptional activation function of p73 is specifically targeted by E1A through a mechanism involving p300/CBP proteins during the process of transformation and that p73 may have a role to play as a tumor suppressor.