Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential
Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential
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DOI：
10.1038/sj.onc.1209323
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发表时间：
2006-05-01
期刊：
影响因子：
8
通讯作者：
Huebner, K.
中科院分区：
文献类型：
--
作者：
Semba, S.;Trapasso, F.;Huebner, K.
Fhit肿瘤抑制因子结合并水解二腺苷多磷酸，并且Fhit -底物复合物已被提出作为促凋亡效应物，如通过用携带野生型脆性组氨酸三联体（FHIT）或催化位点突变体的腺病毒感染易感癌细胞所确定的.高度保守的Fhit酪氨酸114（Y114）位于催化位点的非结构化环C-末端内，可被Src家族酪氨酸激酶磷酸化，尽管内源性磷酸化Fhit很少被检测到。为了探索Y114的重要性并鉴定FHIT介导的信号传导事件，将表达野生型和Y114突变体FHIT的腺病毒导入两种人肺癌细胞系中.半胱天冬酶依赖性细胞凋亡有效地诱导只有野生型，而不是Y114突变体Fhit蛋白。通过FHIT与突变FHIT感染细胞的表达变化，我们发现野生型Fhit显着降低了细胞凋亡蛋白抑制剂（IAP）家族成员生存素的表达。此外，Fhit抑制Akt的活性，Akt是磷脂酰肌醇3- OH激酶（PI 3 K）通路中的关键效应子;内源性Fhit表达的丧失导致体外和体内Akt活性增加，组成性活性Akt的过表达抑制Fhit诱导的细胞凋亡。结果表明，FhitY 114残基在Fhit诱导的细胞凋亡中起关键作用，通过PI 3 K-Akt-生存素信号通路的失活而发生.
The Fhit tumor suppressor binds and hydrolyses diadenosine polyphosphates and the Fhit - substrate complex has been proposed as a proapoptotic effector, as determined by infection of susceptible cancer cells with adenoviruses carrying wild- type fragile histidine triad ( FHIT) or catalytic site mutants. The highly conserved Fhit tyrosine 114 ( Y114), within the unstructured loop C- terminal of the catalytic site, can be phosphorylated by Src family tyrosine kinases, although endogenous phospho- Fhit is rarely detected. To explore the importance of Y114 and identify Fhit- mediated signaling events, wild- type and Y114 mutant FHIT- expressing adenoviruses were introduced into two human lung cancer cell lines. Caspase-dependent apoptosis was effectively induced only by wildtype but not Y114 mutant Fhit proteins. By expression proling of FHIT versus mutant FHIT- infected cells, we found that survivin, an Inhibitor of Apoptosis Protein ( IAP) family member, was significantly decreased by wildtype Fhit. In addition, Fhit inhibited activity of Akt, a key effector in the phosphatidylinositol 3- OH kinase ( PI3K) pathway; loss of endogenous Fhit expression caused increased Akt activity in vitro and in vivo, and overexpression of constitutively active Akt inhibited Fhit-induced apoptosis. The results indicate that the Fhit Y114 residue plays a critical role in Fhit- induced apoptosis, occurring through inactivation of the PI3K- Akt- survivin signal pathway.