PTEN regulates DNA replication progression and stalled fork recovery

He, Jin-Xue; Kang, Xi; Yin, Yuxin; Chao, K.; Shen, Wen Hong

doi:10.1038/ncomms8620

Cited by 77 publications

(93 citation statements)

References 31 publications

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“…In addition, deletion of PTEN can initiate a replication stress cascade and thus regulate the cell cycle. 23 PTEN-L is a secretory translational variant. It has an additional 173 aa at the N terminus of PTEN.…”

Section: Pten and Tumor Suppressionmentioning

confidence: 99%

The functions of tumor suppressor PTEN in innate and adaptive immunity

Chen

Guo

2017

Cell Mol Immunol

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The tumor suppressor phosphatase and tensin homolog (PTEN) is a lipid and protein phosphatase that is able to antagonize the PI3K/AKT pathway and inhibit tumor growth. PTEN also possesses phosphatase-independent functions. Genetic alterations of PTEN may lead to the deregulation of cell proliferation, survival, differentiation, energy metabolism and cellular architecture and mobility. Although the role of PTEN in tumor suppression is extensively documented and well established, the evidence for its roles in immunity did not start to accumulate until recently. In this review, we will focus on the newly discovered functions of PTEN in the regulation of innate and adaptive immunity, including antiviral responses.

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Section: Pten and Tumor Suppressionmentioning

confidence: 99%

The functions of tumor suppressor PTEN in innate and adaptive immunity

Chen

Guo

2017

Cell Mol Immunol

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“…[1][2][3][4] PTEN targets phosphatidylinositol-3,4,5-triphosphate (PIP3) and antagonizes the major survival pathway regulated by phosphatidylinositol 3-kinase (PI3K)/Akt. [5][6][7] Increasing evidence indicates that nuclear PTEN has fundamental functions in maintenance of chromosomal stability, 2,[8][9][10][11][12][13][14] suggesting there are as yet unidentified mechanisms in the process of chromosome inheritance for which the function of PTEN is indispensable. It has been shown that PTEN plays an essential role in maintaining the structural integrity of individual chromosomes, 2 which supports recognition of PTEN as a guardian of the genome.…”

Section: Introductionmentioning

confidence: 99%

PTEN regulates PLK1 and controls chromosomal stability during cell division

Zhang

Hou

et al. 2016

Cell Cycle

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PTEN functions as a guardian of the genome through multiple mechanisms. We have previously established that PTEN maintains the structural integrity of chromosomes. In this report, we demonstrate a fundamental role of PTEN in controlling chromosome inheritance to prevent gross genomic alterations. Disruption of PTEN or depletion of PTEN protein phosphatase activity causes abnormal chromosome content, manifested by enlarged or polyploid nuclei. We further identify polo-like kinase 1 (PLK1) as a substrate of PTEN phosphatase. PTEN can physically associate with PLK1 and reduce PLK1 phosphorylation in a phosphatase-dependent manner. We show that PTEN deficiency leads to PLK1 phosphorylation and that a phospho-mimicking PLK1 mutant causes polyploidy, imitating functional deficiency of PTEN phosphatase. Inhibition of PLK1 activity or overexpression of a non-phosphorylatable PLK1 mutant reduces the polyploid cell population. These data reveal a new mechanism by which PTEN controls genomic stability during cell division.

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“…Loss of PTEN expression results in Rad51 dissociation from DNA replication forks, and subsequent destabilization and stalled replication. Cells lacking PTEN have deficient HRR functions, likely due to reduced Rad51 recruitment to the replicating DNA, culminating in loss of fidelity during DNA synthesis (44). As with BRCA1/2 mutations, cells lacking PTEN function are prone to HRR deficiencies and, subsequently, have been shown to be sensitive to PARPi (45,46).…”

Section: Discussionmentioning

confidence: 99%

Synthetic Lethality Exploitation by an Anti–Trop-2-SN-38 Antibody–Drug Conjugate, IMMU-132, Plus PARP Inhibitors in BRCA1/2–wild-type Triple-Negative Breast Cancer

Cardillo

Sharkey

Rossi

et al. 2017

Clinical Cancer Research

104

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Purpose: Both PARP inhibitors (PARPi) and sacituzumab govitecan are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)-inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC.Experimental Design: In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, doublestranded DNA (dsDNA) breaks, and cell-cycle arrest. Mice bearing BRCA1/2-mutated or -wild-type human TNBC tumor xenografts were treated with the combination of IMMU-132 and PARPi (olaparib or talazoparib). Study survival endpoint was tumor progression to >1.0 cm 3 and tolerability assessed by hematologic changes.Results: Combining IMMU-132 in TNBC with all three different PARPi results in synergistic growth inhibition, increased dsDNA breaks, and accumulation of cells in the Sphase of the cell cycle, regardless of BRCA1/2 status. A combination of IMMU-132 plus olaparib or talazoparib produces significantly improved antitumor effects and delay in time-totumor progression compared with monotherapy in mice bearing BRCA1/2-mutated HCC1806 TNBC tumors. Furthermore, in mice bearing BRCA1/2-wild-type tumors (MDA-MB-468 or MDA-MB-231), the combination of IMMU-132 plus olaparib imparts a significant antitumor effect and survival benefit above that achieved with monotherapy. Most importantly, this combination was well tolerated, with no substantial changes in hematologic parameters.Conclusions: These data demonstrate the added benefit of combining Topo I inhibition mediated by IMMU-132 with synthetic lethality provided by PARPi in TNBC, regardless of BRCA1/2 status, thus supporting the rationale for such a combination clinically. Clin Cancer Res; 23(13); 3405-15. Ó2017 AACR.

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PTEN regulates DNA replication progression and stalled fork recovery

Cited by 77 publications

References 31 publications

The functions of tumor suppressor PTEN in innate and adaptive immunity

The functions of tumor suppressor PTEN in innate and adaptive immunity

PTEN regulates PLK1 and controls chromosomal stability during cell division

Synthetic Lethality Exploitation by an Anti–Trop-2-SN-38 Antibody–Drug Conjugate, IMMU-132, Plus PARP Inhibitors in BRCA1/2–wild-type Triple-Negative Breast Cancer

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