PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation.
PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation.
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PBK/TOPK 介导乳腺癌细胞增殖的香叶基香叶基化信号传导。
DOI：
10.1186/s12935-015-0178-0
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发表时间：
2015
影响因子：
5.8
通讯作者：
Lin Q
中科院分区：
文献类型：
--
作者：
Dou X;Wei J;Sun A;Shao G;Childress C;Yang W;Lin Q
PDZ结合激酶（PDZ binding-kinase，PBK），又称T淋巴因子激活的杀伤细胞源性蛋白激酶（T-lymphokine-activated killer cell-originated protein kinase，TOPK），是一种丝氨酸/苏氨酸激酶，在正常组织中受到严格控制，但在许多肿瘤中升高，在肿瘤的发生和转移中起作用。然而，调节癌细胞中PI 3 K表达的信号传导仍然难以捉摸。在这里，我们表明，阿托伐他汀（立普妥），羟甲基戊二酰辅酶A（HMG-CoA）还原酶，是甲羟戊酸途径的限速酶的抑制剂，下调蛋白质香叶基香叶基化的表达。shRNA敲除证实了Yes相关蛋白（雅普）介导了香叶基香叶基化调控的PBK表达。重要的是，阿托伐他汀或香叶基香叶基转移酶I抑制剂GGTI-298通过灭活雅普信号和下调PI 3 K抑制乳腺癌细胞增殖。这些发现明确了一条新的调控PBK表达的信号通路，并将PBK确定为Hippo-YAP信号通路的下游靶点，揭示了通过抑制甲羟戊酸通路和香叶基香叶基化发挥抗肿瘤作用的机制，为乳腺癌靶向治疗提供了潜在的靶点。
PDZ binding-kinase (PBK) (also named T-lymphokine-activated killer cell-originated protein kinase (TOPK)), a serine/threonine kinase, is tightly controlled in normal tissues but elevated in many tumors, and functions in tumorigenesis and metastasis. However, the signaling that regulates expression of PBK in cancer cells remains elusive. Here we show that atorvastatin (Lipitor), an inhibitor of hydroxymethylglutaryl co-enzyme A (HMG-CoA) reductase that is a rate-limiting enzyme of mevalonate pathway, down-regulates expression of PBK by impairing protein geranylgeranylation. The shRNA knockdown demonstrated that Yes-associated protein (YAP) mediates geranylgeranylation-regulated expression of PBK. Importantly, atorvastatin or the geranylgeranyltransferase I inhibitor GGTI-298 inhibited breast cancer cell proliferation through inactivation of YAP signaling and down-regulation of PBK. These findings have defined a new signaling pathway that regulated expression of PBK and identified PBK as a downstream target of the Hippo-YAP signaling, uncoverd a mechanism underlying the anti-cancer effect by inhibition of mevalonate pathway and geranylgeranylation, and provided a potential target for breast cancer targeted therapy.
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DOI：
10.1073/pnas.090102397
发表时间：
2000-05-09
影响因子：
11.1
作者：
Gaudet, S;Branton, D;Lue, RA
通讯作者：
Lue, RA
影响因子：
8
作者：
Hu, F.;Gartenhaus, R. B.;Rapoport, A. P.
通讯作者：
Rapoport, A. P.
影响因子：
2.8
作者：
Singh, P. K.;Srivastava, Anupam K.;Bhatt, M. L. B.
通讯作者：
Bhatt, M. L. B.
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
影响因子：
7.4
作者：
Shiraishi T;Terada N;Zeng Y;Suyama T;Luo J;Trock B;Kulkarni P;Getzenberg RH
通讯作者：
Getzenberg RH