Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes.

Zhang, Hui; Xiong, Yue; Beach, David

doi:10.1091/mbc.4.9.897

Cited by 335 publications

(225 citation statements)

References 62 publications

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“…Studies indicated that p21 interacts with the proliferating cell nuclear antigen (PCNA). This p21/ PCNA interaction could inhibit the process of DNA synthesis, which is a major process in DNA damage repair, leading to an arrest in the G 2 -M phase (40)(41)(42). Moreover, we found that lower concentration of dual PI3K/mTOR inhibitors alone slightly induced apoptosis.…”

Section: Discussionmentioning

confidence: 67%

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Liu

Sun

et al. 2015

Molecular Cancer Therapeutics

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Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual g-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR).Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration-and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G 2 -M cellcycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. Mol Cancer Ther; 14(2); 429-39. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 67%

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Liu

Sun

et al. 2015

Molecular Cancer Therapeutics

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“…Among these factors there are negative regulators of cell growth, the CDK inhibitors (CDIs). Expression of one of them, p21 (WAF1/CIP1/CDKN1), a universal component of cyclin-CDK complexes (Zhang et al, 1993), is frequently abolished by mutational or viral inactivation of its positive regulator p53 in many tumors (ElDeiry et al, 1993;Hollstein et al, 1991). A key role in the regulation of S-phase entry of a cell is played by the product of the Rb tumor suppressor gene pRB.…”

Section: Introductionmentioning

confidence: 99%

Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors

et al. 1997

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The pRB cell cycle regulatory cascade is frequently perturbed in neoplasia by overexpression of a component of the pRB-phosphorylating cyclin D1/CDK4 complex or by inactivation of pRB or the CDK4 inhibitors p16 and p15. We investigated the status and expression of p16, p15, CCND1, CDK4 and RB genes in the Ewing family of tumors. P16 loss was observed in 8 of 27 tumors (30%) and in 12 of 23 (52%) tumor cell lines from unrelated patients. There were no discrepancies in the p16 status between primary tumors and the corresponding cell lines and between cell lines established from consecutive tumor samples. p15 was codeleted in most cases but p15 mRNA was absent also in cell lines retaining the gene. In addition, posttranscriptional p16 inactivation was observed in two cases. Although no evidence for CDK4 or CCND1 ampli®cation was obtained, expression of these genes varied considerably in the cell lines in a case speci®c manner. In wild-type p16 cell lines, pRB expression was lost in one case. Our data indicate that, despite the absence of cytogenetically detectable 9p21 chromosomal aberrations, p16 deletions constitute the most frequent secondary molecular aberration in Ewing tumors so far. These results are discussed in the context of the stage of disease and the clinical outcome of the patients. The potential prognostic impact of these ®ndings remains to be further evaluated.

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“…PCNA forms a quaternary complex with CDK, cyclin D, and p21, suggesting that PCNA may play an important role in cell cycle regulation beyond its function in the DNA replication machinery (13)(14)(15). CDKs regulate progression through the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Proliferating Cell Nuclear Antigen as the Cell Cycle Sensor for an HLA-Derived Peptide Blocking T Cell Proliferation

Ling

Kamangar

Boytim³

et al. 2000

The Journal of Immunology

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Synthetic peptides corresponding to structural regions of HLA molecules are novel immunosuppressive agents. A peptide corresponding to residues 65–79 of the α-chain of HLA-DQA03011 (DQ65–79) blocks cell cycle progression from early G1 to the G1 restriction point, which inhibits cyclin-dependent kinase-2 activity and phosphorylation of the retinoblastoma protein. A yeast two-hybrid screen identified proliferating cell nuclear Ag (PCNA) as a cellular ligand for this peptide, whose interaction with PCNA was further confirmed by in vitro biochemistry. Electron microscopy demonstrates that the DQ65–79 peptide enters the cell and colocalizes with PCNA in the T cell nucleus in vivo. Binding of the DQ65–79 peptide to PCNA did not block polymerase δ (pol δ)-dependent DNA replication in vitro. These findings support a key role for PCNA as a sensor of cell cycle progression and reveal an unanticipated function for conserved regions of HLA molecules.

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Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes.

Cited by 335 publications

References 62 publications

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors

Proliferating Cell Nuclear Antigen as the Cell Cycle Sensor for an HLA-Derived Peptide Blocking T Cell Proliferation

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