Poly (ADP-Ribose) Transferase/Polymerase-1-Deficient Mice Resistant to Age-Dependent Decrease in β-Cell Proliferation

Gong, Lei; Liu, Fuqiang; Wang, Ying; Hou, Xinguo; Zhang, Wei; Qin, Weidong; Zhang, Yun; Chen, Li; Zhang, Mingxiang

doi:10.2119/molmed.2011.00458

Cited by 5 publications

(7 citation statements)

References 38 publications

(48 reference statements)

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“…Several recent studies have reported that PARP-1 could negatively regulate bone resorption and that PARP inhibition could suppress the osteogenic differentiation of osteosarcoma cells and mouse mesenchymal stem cells 18,19 . We have shown that PARP-1 functions as a crucial modulator of NF-kB activity and that PARP-1 inhibition attenuates inflammatory responses during atherogenesis 20,21 and diabetic complications 22 . However, the potential link between PARP-1 regulation and diabetes-induced atherosclerotic calcification has not been examined.…”

Section: Introductionmentioning

confidence: 99%

Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis

Wang

Liu

et al. 2020

Cell Death Dis

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Accelerated atherosclerotic calcification is responsible for plaque burden, especially in diabetes. The regulatory mechanism for atherosclerotic calcification in diabetes is poorly characterized. Here we show that deletion of PARP-1, a main enzyme in diverse metabolic complications, attenuates diabetic atherosclerotic calcification and decreases vessel stiffening in mice through Runx2 suppression. Specifically, PARP-1 deficiency reduces diabetic arteriosclerotic calcification by regulating Stat1-mediated synthetic phenotype switching of vascular smooth muscle cells and macrophage polarization. Meanwhile, both vascular smooth muscle cells and macrophages manifested osteogenic differentiation in osteogenic media, which was attenuated by PARP-1/Stat1 inhibition. Notably, Stat1 acts as a positive transcription factor by directly binding to the promoter of Runx2 and promoting atherosclerotic calcification in diabetes. Our results identify a new function of PARP-1, in which metabolism disturbance-related stimuli activate the Runx2 expression mediated by Stat1 transcription to facilitate diabetic arteriosclerotic calcification. PARP-1 inhibition may therefore represent a useful therapy for this challenging complication.

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Section: Introductionmentioning

confidence: 99%

Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis

Wang

Liu

et al. 2020

Cell Death Dis

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“…Mammalian PARP-1 is a 116-kDa protein that catalyzes the covalent attachment of poly(ADP-ribose) polymers on itself and on other acceptor proteins (16). PARP-1 contains three major functional units, including the DNA-binding domain comprised of two zinc finger motifs, the automodification domain that functions as the target of covalent automodification, and the catalytic domain (17).…”

Section: Biochemical Identification Of the Allele-binding Nuclear Actmentioning

confidence: 99%

An Infectious Disease–Associated Il12b Polymorphism Regulates IL-12/23 p40 Transcription Involving Poly(ADP-Ribose) Polymerase 1

Zhao

Wei

et al. 2017

The Journal of Immunology

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IL-12 and IL-23 are important host defense factors produced by APCs against certain intracellular and extracellular pathogens. Their dysregulation has also been implicated in several autoimmune diseases. The nucleotide polymorphism in the promoter region of (rs41292470 consisting of the long or short allele) encoding the shared subunit of IL-12 and IL-23, p40, has been reported to associate with susceptibility to infectious diseases and autoimmune disorders. How these genetic variants impact expression at the molecular level was unclear. We established an promoter-luciferase reporter system containing the long or short allele driving the reporter gene expression and found that the long allele (infection-resistant) displayed ∼2-fold higher transcriptional activity than the short allele (infection-susceptible), associated with a selective and differential nuclear binding activity to the two alleles in activated macrophages. DNA pull-down assays coupled with mass spectrometry analyses identified the specific DNA binding activity as poly(ADP-ribose) polymerase 1 (PARP-1). Small hairpin RNA-mediated knockdown of the endogenous PARP-1 expression resulted in reduced p40 mRNA expression and promoter activity. Bone marrow-derived macrophages from PARP-1-deficient mice had decreased p40 expression at both mRNA and protein levels. Furthermore, selective PARP-1 inhibitors resulted in impaired production of IL-12p40 and IL-23 in bone-marrow derived macrophages and PBMCs. Chromatin immunoprecipitation assay revealed that PARP-1 could bind specifically to in LPS-stimulated macrophages. Our study opens the way for further elucidating the molecular mechanism whereby allele-specific immune responses to foreign and self-antigens mediated by IL-12/IL-23 are controlled in an individually variable manner.

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“…To assess and distinguish between the roles of PARP1 protein and its activity in the stem cell-mediated islet regeneration potential, we first compared pancreatic histology for islet development in PARP1 knockout and wild-type mice produced in the 129SV-B6 strain background. An age-dependent study from Zhang et al 22 has reported no effect of PARP-1 deletion on glucose homeostasis and functional regulation of β cells in young and old KO mice despite the whole body PARP1 knockout. Considering non-affected glucose metabolism, we expanded our investigation to delineate the developmental aspects of islet formation and pancreas architecture in PARP1 wild-type and KO mice.…”

Section: Resultsmentioning

confidence: 99%

“…The role of PARPs in diabetes has been explored for the last thirty years, with early studies employing PARP-inhibitors in isolated β cell function 15 , 34 , while later reports investigated the action using PARP1 −/− mice or derived cells 17 – 20 . The prime emphasis was, however, overlaid on PARP1 for exploring the role in DNA repair during β cell death, survival, physiology, and insulin secretion 6 , 22 , 29 . Moreover, most minor attempts were made to understand the possible mode of action of PARP1 in β cell regeneration or stem cell-derived differentiation.…”

Section: Discussionmentioning

confidence: 99%

Role of poly(ADP-ribose) polymerase-1 in regulating human islet cell differentiation

Dadheech

Srivastava

Shah

et al. 2022

Sci Rep

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Poly(ADP-ribose) polymerase-1 (PARP1), a fundamental DNA repair enzyme, is known to regulate β cell death, replication, and insulin secretion. PARP1 knockout (KO) mice are resistant to diabetes, while PARP1 overactivation contributes to β cell death. Additionally, PARP1 inhibition (PARPi) improves diabetes complications in patients with type-2 diabetes. Despite these beneficial effects, the use of PARP1 modulating agents in diabetes treatment is largely neglected, primarily due to the poorly studied mechanistic action of PARP1 catalytic function in human β cell development. In the present study, we evaluated PARP1 regulatory action in human β cell differentiation using the human pancreatic progenitor cell line, PANC-1. We surveyed islet census and histology from PARP1 wild-type versus KO mice pancreas in a head-to-head comparison with PARP1 regulatory action for in-vitro β cell differentiation following either PARP1 depletion or its pharmacological inhibition in PANC-1-differentiated islet cells. shRNA mediated PARP1 depleted (SiP) and shRNA control (U6) PANC-1 cells were differentiated into islet-like clusters using established protocols. We observed complete abrogation of new β cell formation with absolute PARP1 depletion while its inhibition using the potent inhibitor, PJ34, promoted the endocrine β cell differentiation and maturation. Immunohistochemistry and immunoblotting for key endocrine differentiation players along with β cell maturation markers highlighted the potential regulatory action of PARP1 and augmented β cell differentiation due to direct interaction of unmodified PARP1 protein elicited p38 MAPK phosphorylation and Neurogenin-3 (Ngn3) re-activation. In summary, our study suggests that PARP1 is required for the proper development and differentiation of human islets. Selective inhibition with PARPi can be an advantage in pushing more insulin-producing cells under pathological conditions and delivers a potential for pilot clinical testing for β cell replacement cell therapies for diabetes.

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Poly (ADP-Ribose) Transferase/Polymerase-1-Deficient Mice Resistant to Age-Dependent Decrease in β-Cell Proliferation

Cited by 5 publications

References 38 publications

Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis

Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis

An Infectious Disease–Associated Il12b Polymorphism Regulates IL-12/23 p40 Transcription Involving Poly(ADP-Ribose) Polymerase 1

Role of poly(ADP-ribose) polymerase-1 in regulating human islet cell differentiation

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