PI3K stimulates DNA synthesis and cell-cycle progression via its p55PIK regulatory subunit interaction with PCNA.
Previously, we have shown that p55PIK, an isoform of class I(A) phosphoinositide 3-kinase (PI3K), specifically interacts with important cell-cycle regulators, such as retinoblastoma (Rb), to promote cell-cycle progression. Here, we used the glutathione S-transferase pull-down assay to identify other p55PIK-interacting proteins besides Rb in a Rb-deficient cell line and found that p55PIK interacted with proliferation cell nuclear antigen (PCNA), which plays a key role in coordinating both initiation of the leading strand DNA replication and discontinuous lagging strand synthesis. Overexpression of p55PIK increased, and knockdown decreased, DNA synthesis and DNA replication by modulating the binding of DNA polymerase δ (Polδ) to PCNA. Moreover, a cell-permeable peptide containing the N-terminal-binding domain of p55PIK (TAT-N24) disrupted the p55PIK-PCNA interaction in cancer cells, and also inhibited the DNA synthesis and tumor growth in cell culture and in vivo. Altogether, our results show that the p55PIK-PCNA interaction is important in regulating DNA synthesis and contributes to tumorigenesis. Furthermore, the p55PIK-PCNA interaction provides a potential new target for anticancer drug development.
Corresponding Authors: Junbo Hu, Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan 430030, China. jbhu@tjh.tjmu.edu.cn.
Guihua
G
Wang
Xiaonian
X
Cao
Senyan
S
Lai
Xuelai
X
Luo
Yongdong
Y
Feng
Xianmin
X
Xia
Paul M
PM
Yen
Jianping
J
Gong
Junbo
J
Hu
D063646:Carcinogenesis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000235:genetics; D053492:Elafin / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000235:genetics
D053492:Elafin; C506806:PI3 protein, human; D018809:Proliferating Cell Nuclear Antigen; D004247:DNA; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; C523442:PIK3R3 protein, human