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Putative proto-oncogene Pir expression is significantly up-regulated in the spleen and kidney of cytosolic superoxide dismutase-deficient mice.

ABSTRACT: Iron binding protein pirin was isolated as an interactor of the NFIX transcription factor but it can also form complexes with Bcl3 and NF-?B1(p50). Alterations of pirin expression were observed in various tumors and after exposure to pro-carcinogenic oxidative stressors. The aim of the present work was to study the level of pirin transcription in an in vivo model of oxidative stress, namely, in Sod1-deficient mice. We have found that Sod1(-/-) mice have a significantly elevated level of Pir mRNA in the spleen and kidney but not in the liver, heart, or/and brain. We have also shown that similarly to its human ortholog, the mouse Pir gene transcription level varies significantly between organs. The highest expression was found in the liver and the lowest in the spleen and kidney. Based on literature data, we propose the involvement of Nrf2, AP-1, and NF-?B transcription factors in Pir up-regulation in Sod1(-/-) mice.

SUBMITTER: Brzoska K

PROVIDER: S-EPMC6837407 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Putative proto-oncogene Pir expression is significantly up-regulated in the spleen and kidney of cytosolic superoxide dismutase-deficient mice.

Brzóska Kamil K Stępkowski Tomasz M TM Kruszewski Marcin M

Redox report : communications in free radical research 20110101 3

Iron binding protein pirin was isolated as an interactor of the NFIX transcription factor but it can also form complexes with Bcl3 and NF-κB1(p50). Alterations of pirin expression were observed in various tumors and after exposure to pro-carcinogenic oxidative stressors. The aim of the present work was to study the level of pirin transcription in an in vivo model of oxidative stress, namely, in Sod1-deficient mice. We have found that Sod1(-/-) mice have a significantly elevated level of Pir mRNA ...[more]

PMID: 21801495

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Project description:Over 130 mutations to copper, zinc superoxide dismutase (SOD) are implicated in the selective death of motor neurons found in 25% of patients with familial amyotrophic lateral sclerosis (ALS). Despite their widespread distribution, ALS mutations appear positioned to cause structural and misfolding defects. Such defects decrease SOD's affinity for zinc, and loss of zinc from SOD is sufficient to induce apoptosis in motor neurons in vitro. To examine the importance of the zinc site in the structure and pathogenesis of human SOD, we determined the 2.0-A-resolution crystal structure of a designed zinc-deficient human SOD, in which two zinc-binding ligands have been mutated to hydrogen-bonding serine residues. This structure revealed a 9 degrees twist of the subunits, which opens the SOD dimer interface and represents the largest intersubunit rotational shift observed for a human SOD variant. Furthermore, the electrostatic loop and zinc-binding subloop were partly disordered, the catalytically important Arg143 was rotated away from the active site, and the normally rigid intramolecular Cys57-Cys146 disulfide bridge assumed two conformations. Together, these changes allow small molecules greater access to the catalytic copper, consistent with the observed increased redox activity of zinc-deficient SOD. Moreover, the dimer interface is weakened and the Cys57-Cys146 disulfide is more labile, as demonstrated by the increased aggregation of zinc-deficient SOD in the presence of a thiol reductant. However, equimolar Cu,Zn SOD rapidly forms heterodimers with zinc-deficient SOD (t1/2 approximately 15 min) and prevents aggregation. The stabilization of zinc-deficient SOD as a heterodimer with Cu,Zn SOD may contribute to the dominant inheritance of ALS mutations. These results have general implications for the importance of framework stability on normal metalloenzyme function and specific implications for the role of zinc ion in the fatal neuropathology associated with SOD mutations.

Dataset Information

Putative proto-oncogene Pir expression is significantly up-regulated in the spleen and kidney of cytosolic superoxide dismutase-deficient mice.

Publications

Putative proto-oncogene Pir expression is significantly up-regulated in the spleen and kidney of cytosolic superoxide dismutase-deficient mice.

Similar Datasets

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