Polymerase δ-interacting Protein 2: A Multifunctional Protein

Hernandes, Marina S.; Lassègue, Bernard; Griendling, Kathy K.

doi:10.1097/fjc.0000000000000465

Cited by 28 publications

(36 citation statements)

References 48 publications

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“…Poldip2 is a multifunctional protein that has no homology to other known mammalian proteins, consisting of an N-terminal mitochondrial targeting sequence and two main functional domains: a DUF525 domain and a YccV-like domain. 24 Although Poldip2 is transcribed from a single gene, its mitochondrial targeting sequence results in cleavage of the 42-kDa protein to a 37-kDa form. Poldip2 binds to a variety of proteins, including p22phox, 25 polymerase-δ and PCNA, 6, 9 and carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1).…”

Section: Discussionmentioning

confidence: 99%

Poldip2 knockdown inhibits vascular smooth muscle proliferation and neointima formation by regulating the expression of PCNA and p21

Datla

Hilenski

Seidel-Rogol

et al. 2019

Laboratory Investigation

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Polymerase delta interacting protein 2 (Poldip2) is a multi-functional protein with numerous roles in the vasculature, including the regulation of cell apoptosis and migration as well as extracellular matrix deposition; however, its role in VSMC proliferation and neointimal formation is unknown. In this study, we investigated the role of Poldip2 in intraluminal wire-injury induced neointima formation and proliferation of vascular smooth muscle cells in vitro and in vivo. Poldip2 expression was observed in the intima and media of human atherosclerotic arteries, where it colocalized with proliferating cell nuclear antigen (PCNA). Wire injury of femoral arteries of Poldip2 +/+ mice induced robust neointimal formation after two weeks, which was impaired in Poldip2 +/− mice. PCNA expression was significantly reduced and expression of the cell cycle inhibitor p21 was significantly increased in wire-injured arteries of Poldip2 +/− animals compared to wild type controls. No difference was observed in apoptosis. Down-regulation of Poldip2 in rat aortic smooth muscle cells significantly reduced serum-induced proliferation and PCNA expression, but upregulated p21 expression. Downregulation of p21 using siRNA reversed the inhibition of proliferation induced by knock down of Poldip2. These results indicate that Poldip2 plays a critical role in the proliferation of VSMCs.

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Section: Discussionmentioning

confidence: 99%

Poldip2 knockdown inhibits vascular smooth muscle proliferation and neointima formation by regulating the expression of PCNA and p21

Datla

Hilenski

Seidel-Rogol

et al. 2019

Laboratory Investigation

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“…5 ). In addition, Poldip2 has a number of binding partners [ 54 ], verified and unverified, that may explain why loss of Poldip2 affects BBB permeability without affording neuroprotection. Nonetheless, protection against BBB permeability is likely to be physiologically important, given the decreased mortality and improved motor function in Poldip2 +/− mice compared to Poldip2 +/+ mice 24 h after cerebral ischemia.…”

Section: Discussionmentioning

confidence: 99%

Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain

Hernandes

Lassègue

Hilenski

et al. 2018

J Neuroinflammation

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BackgroundPolymerase δ-interacting protein 2 (Poldip2) is a multifunctional protein that regulates vascular extracellular matrix composition and matrix metalloproteinase (MMP) activity. The blood-brain barrier (BBB) is a dynamic system assembled by endothelial cells, basal lamina, and perivascular astrocytes, raising the possibility that Poldip2 may be involved in maintaining its structure. We investigated the role of Poldip2 in the late BBB permeability induced by cerebral ischemia.MethodsTransient middle cerebral artery occlusion (tMCAO) was induced in Poldip2+/+ and Poldip2+/− mice. The volume of the ischemic lesion was measured in triphenyltetrazolium chloride-stained sections. BBB breakdown was evaluated by Evans blue dye extravasation. Poldip2 protein expression was evaluated by western blotting. RT-PCR, zymography, and ELISAs were used to measure mRNA levels, activity, and protein levels of cytokines and MMPs. Cultured astrocytes were transfected with Poldip2 siRNA, and mRNA levels of cytokines were evaluated as well as IκBα protein degradation.ResultsCerebral ischemia induced the expression of Poldip2. Compared to Poldip2+/+ mice, Poldip2+/− animals exhibited decreased Evans blue dye extravasation and improved survival 24 h following stroke. Poldip2 expression was upregulated in astrocytes exposed to oxygen and glucose deprivation (OGD) and siRNA-mediated downregulation of Poldip2 abrogated OGD-induced IL-6 and TNF-α expression. In addition, siRNA against Poldip2 inhibited TNF-α-induced IκBα degradation. TNF-α, IL-6, MCP-1, VEGF, and MMP expression induced by cerebral ischemia was abrogated in Poldip2+/− mice. The protective effect of Poldip2 depletion on the increased permeability of the BBB was partially reversed by systemic administration of TNF-α.ConclusionsPoldip2 is upregulated following ischemic stroke and mediates the breakdown of the BBB by increasing cerebral cytokine production and MMP activation. Therefore, Poldip2 appears to be a promising novel target for the development of therapeutic strategies to prevent the development of cerebral edema in the ischemic brain.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1032-1) contains supplementary material, which is available to authorized users.

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“…In U2OS cells, it is estimated that there are about 70,000 molecules of PDIP38 and less than 500 molecules of Pol η ( Beck et al., 2011 ). However, caution should be taken as most of PDIP38 molecules are localized in the cytosol and mitochondria, although PDIP38 can be shuttled between the nucleus and cytosol ( Hernandes et al., 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis

et al. 2018

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SummaryThere are significant ambiguities regarding how DNA polymerase η is recruited to DNA lesion sites in stressed cells while avoiding normal replication forks in non-stressed cells. Even less is known about the mechanisms responsible for Pol η-induced mutations in cancer genomes. We show that there are two safeguards to prevent Pol η from adventitious participation in normal DNA replication. These include sequestration by a partner protein and low basal activity. Upon cellular UV irradiation, phosphorylation enables Pol η to be released from sequestration by PDIP38 and activates its polymerase function through increased affinity toward monoubiquitinated proliferating cell nuclear antigen (Ub-PCNA). Moreover, the high-affinity binding of phosphorylated Pol η to Ub-PCNA limits its subsequent displacement by Pol δ. Consequently, activated Pol η replicates DNA beyond the lesion site and potentially introduces clusters of mutations due to its low fidelity. This mechanism could account for the prevalence of Pol η signatures in cancer genome.

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Polymerase δ-interacting Protein 2: A Multifunctional Protein

Cited by 28 publications

References 48 publications

Poldip2 knockdown inhibits vascular smooth muscle proliferation and neointima formation by regulating the expression of PCNA and p21

Poldip2 knockdown inhibits vascular smooth muscle proliferation and neointima formation by regulating the expression of PCNA and p21

Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain

Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis

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