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NF-?B activity during pancreas development regulates adult ?-cell mass by modulating neonatal ?-cell proliferation and apoptosis.

ABSTRACT: NF-?B is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in ?-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-?B in vivo, we have generated two transgenic mouse models, the ToI? and NOD/ToI? mice, in which NF-?B activation is specifically and conditionally inhibited in ?-cells. In this study, we present a novel function of the canonical NF-?B pathway during murine islet ?-cell development. Interestingly, inhibiting the NF-?B pathway in ?-cells during embryogenesis, but not after birth, in both ToI? and NOD/ToI? mice, increased ?-cell turnover, ultimately resulting in a reduced ?-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-?B p65-subunit was found in neonatal ?-cells, significant activation was not detected in ?-cells of either adult NOD/ToI? mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToI? mice, inhibiting NF-?B post-weaning had no effect on the development of diabetes or ?-cell dysfunction. In conclusion, our data point to NF-?B as an important component of the physiological regulatory circuit that controls the balance of ?-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating ?-cell mass and the development of diabetes in the mouse model of T1D.

SUBMITTER: Sever D

PROVIDER: S-EPMC7790827 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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NF-κB activity during pancreas development regulates adult β-cell mass by modulating neonatal β-cell proliferation and apoptosis.

Sever Dror D Hershko-Moshe Anat A Srivastava Rohit R Eldor Roy R Hibsher Daniel D Keren-Shaul Hadas H Amit Ido I Bertuzzi Federico F Krogvold Lars L Dahl-Jørgensen Knut K Ben-Dov Iddo Z IZ Landsman Limor L Melloul Danielle D

Cell death discovery 20210104 1

NF-κB is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in β-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-κB in vivo, we have generated two transgenic mouse models, the ToIβ and NOD/ToIβ mice, in which NF-κB activation is specifically and conditionally inhibited in β-cel ...[more]

PMID: 33414444

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Project description:Hypoxia is caused by a cancer-promoting milieu characterized by persistent inflammation. NF-κB and HIF-1α are critical participants in this transition. Tumor development and maintenance are aided by NF-κB, while cellular proliferation and adaptability to angiogenic signals are aided by HIF-1α. Prolyl hydroxylase-2 (PHD-2) has been hypothesized to be the key oxygen-dependent regulator of HIF-1α and NF-transcriptional B's activity. Without low oxygen levels, HIF-1α is degraded by the proteasome in a process dependent on oxygen and 2-oxoglutarate. As opposed to the normal NF-κB activation route, where NF-κB is deactivated by PHD-2-mediated hydroxylation of IKK, this method actually activates NF-κB. HIF-1α is protected from degradation by proteasomes in hypoxic cells, where it then activates transcription factors involved in cellular metastasis and angiogenesis. The Pasteur phenomenon causes lactate to build up inside the hypoxic cells. As part of a process known as lactate shuttle, MCT-1 and MCT-4 cells help deliver lactate from the blood to neighboring, non-hypoxic tumour cells. Non-hypoxic tumour cells use lactate, which is converted to pyruvate, as fuel for oxidative phosphorylation. OXOPHOS cancer cells are characterized by a metabolic switch from glucose-facilitated oxidative phosphorylation to lactate-facilitated oxidative phosphorylation. Although PHD-2 was found in OXOPHOS cells. There is no clear explanation for the presence of NF-kappa B activity. The accumulation of the competitive inhibitor of 2-oxo-glutarate, pyruvate, in non-hypoxic tumour cells is well established. So, we conclude that PHD-2 is inactive in non-hypoxic tumour cells due to pyruvate-mediated competitive suppression of 2-oxo-glutarate. This results in canonical activation of NF-κB. In non-hypoxic tumour cells, 2-oxoglutarate serves as a limiting factor, rendering PHD-2 inactive. However, FIH prevents HIF-1α from engaging in its transcriptional actions. Using the existing scientific literature, we conclude in this study that NF-κB is the major regulator of tumour cell growth and proliferation via pyruvate-mediated competitive inhibition of PHD-2.

Dataset Information

NF-?B activity during pancreas development regulates adult ?-cell mass by modulating neonatal ?-cell proliferation and apoptosis.

Publications

NF-κB activity during pancreas development regulates adult β-cell mass by modulating neonatal β-cell proliferation and apoptosis.

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