Identification of the Positive Regulatory and Distinct Core Regions of Promoters, and Transcriptional Regulation in Three Types of Mouse Phospholipid Hydroperoxide Glutathione Peroxidase

Imai, Hideki; Saito, Makoto; Kirai, Nozomu; Hasegawa, Junya; Konishi, Kumiko; Hattori, Hiroyuki; Nishimura, Masuhiro; Naito, Shinsaku; Nakagawa, Yasuhito

doi:10.1093/jb/mvj186

Cited by 26 publications

(38 citation statements)

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“…Similar promoter activities were identified in the proximal portions of intron 1a, although n-GPx4 expression is more than two orders of magnitude lower than that of c-and m-GPx4 Imai et al, 2006). Thus, on a quantitative basis it seems to be unlikely that results from the in vitro reporter assays adequately mirror the complex regulatory network of isoform-specific GPx4 expression in vivo.…”

Section: Molecular Mechanisms Of Gpx4 Transcription Regulationmentioning

confidence: 65%

“…This is of particular interest in the context of neurobiology, since these transcription factors are active in developing neurons and reactive astrocytes (Benfante et al, 2005;Bannwarth et al, 2006;Mao et al, 2006). In an attempt to define minimal promoter regions for m-and c-GPx4, various reporter gene assays revealed a complex network of functional interactions between cis-and trans-regulatory elements (Ufer Imai et al, 2006). However, the mechanisms that control the differential selection and strength of transcription initiation sites specific to the GPx4 isoforms remain elusive, since neither spatial arrangements of the transcription initiation complex within the GPx4 promoter nor far distance enhancers or silencers have been analyzed so far.…”

Section: Molecular Mechanisms Of Gpx4 Transcription Regulationmentioning

confidence: 99%

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Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

Savaskan

Ufer

Kühn

et al. 2007

BCHM

115

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Selenoproteins have been recognized as modulators of brain function and signaling. Phospholipid hydroperoxide glutathione peroxidase (GPx4/PHGPx) is a unique member of the selenium-dependent glutathione peroxidases in mammals with a pivotal role in brain development and function. GPx4 exists as a cytosolic, mitochondrial, and nuclear isoform derived from a single gene. In mice, the GPx4 gene is located on chromosome 10 in close proximity to a functional retrotransposome that is expressed under the control of captured regulatory elements. Elucidation of crystallographic data uncovered structural peculiarities of GPx4 that provide the molecular basis for its unique enzymatic properties and substrate specificity. Monomeric GPx4 is multifunctional: it acts as a reducing enzyme of peroxidized phospholipids and thiols and as a structural protein. Transcriptional regulation of the different GPx4 isoforms requires several isoform-specific cis-regulatory sequences and trans-activating factors. Cytosolic and mitochondrial GPx4 are the major isoforms exclusively expressed by neurons in the developing brain. In stark contrast, following brain trauma, GPx4 is specifically upregulated in non-neuronal cells, i.e., reactive astrocytes. Molecular approaches to genetic modification in mice have revealed an essential and isoform-specific function for GPx4 in development and disease. Here we review recent findings on GPx4 with emphasis on its molecular structure and function and consider potential mechanisms that underlie neural development and neuropathological conditions.

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Section: Molecular Mechanisms Of Gpx4 Transcription Regulationmentioning

confidence: 65%

Section: Molecular Mechanisms Of Gpx4 Transcription Regulationmentioning

confidence: 99%

Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

Savaskan

Ufer

Kühn

et al. 2007

BCHM

115

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mentioning

confidence: 99%

“…The GPx4 gene has a complex intron/exon structure (6,7). Three different transcripts of GPx4 exist, differing in their 5Ј extension and coding for a cytosolic protein (non-mitochondrial GPx4), a mitochondrial protein (mitochondrial GPx4), and a nuclear protein (nucleolar GPx4), respectively (6,7). After cleavage of the N-terminal mitochondrial import sequence of mitochondrial GPx4, the mature protein becomes identical to the 20-kDa non-mitochondrial GPx4 (8,9).…”

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confidence: 99%

Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice

Imai

Hakkaku

Iwamoto

et al. 2009

Journal of Biological Chemistry

Self Cite

185

141

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Phospholipid hydroperoxide glutathione peroxidase (GPx4) is an intracellular antioxidant enzyme that directly reduces peroxidized phospholipids. GPx4 is strongly expressed in the mitochondria of testis and spermatozoa. We previously found a significant decrease in the expression of GPx4 in spermatozoa from 30% of infertile human males diagnosed with oligoasthenozoospermia (Imai, H., Suzuki, K., Ishizaka, K., Ichinose, S., Oshima, H., Okayasu, I., Emoto, K., Umeda, M., and Nakagawa, Y. (2001) Biol. Reprod. 64, 674 -683). To clarify whether defective GPx4 in spermatocytes causes male infertility, we established spermatocyte-specific GPx4 knock-out mice using a CreloxP system. All the spermatocyte-specific GPx4 knock-out male mice were found to be infertile despite normal plug formation after mating and displayed a significant decrease in the number of spermatozoa. Isolated epididymal GPx4-null spermatozoa could not fertilize oocytes in vitro. These spermatozoa showed significant reductions of forward motility and the mitochondrial membrane potential. These impairments were accompanied by the structural abnormality, such as a hairpin-like flagella bend at the midpiece and swelling of mitochondria in the spermatozoa. These results demonstrate that the depletion of GPx4 in spermatocytes causes severe abnormalities in spermatozoa. This may be one of the causes of male infertility in mice and humans.A frequent cause of male infertility is defective sperm function, which is the main problem for close to a quarter of couples who attend infertility clinics (1-4). Considerable efforts are now focused on the identifying ultrastructural and/or molecular defects in the spermatozoa or seminal plasma to develop solutions to various types of male infertility.Phospholipid hydroperoxide glutathione peroxidase (GPx4) 2 is an intracellular selenoprotein that directly reduces peroxidized phospholipids produced in cell membranes (5). The GPx4 gene has a complex intron/exon structure (6, 7). Three different transcripts of GPx4 exist, differing in their 5Ј extension and coding for a cytosolic protein (non-mitochondrial GPx4), a mitochondrial protein (mitochondrial GPx4), and a nuclear protein (nucleolar GPx4), respectively (6, 7). After cleavage of the N-terminal mitochondrial import sequence of mitochondrial GPx4, the mature protein becomes identical to the 20-kDa non-mitochondrial GPx4 (8, 9). Nuclear GPx4 was recently identified as a sperm nucleus-specific 34-kDa selenoprotein (called snGPx, for sperm nucleus-specific glutathione peroxidase) (10). It is formed by use of an alternative promoter and start codon localized in the first intron of the GPx4 gene (7, 10, 11). We previously reported that 34-kDa GPx4 localized in nucleoli in several cell lines by using an N-terminal nucleolar import signal (11). We call hereafter nuclear GPx4 nucleolar GPx4, because non-mitochondrial 20-kDa GPx4 exists both in cytosol and in the nucleus (12). Expression of three types of GPx4 is induced significantly in testis during spermatogenesis, especiall...

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“…A complex transcriptional regulation pattern involving interplay between several transcription factors, such as Oct-1, Sp1, and Sp3, and multiple transcription start sites in a cell-and stimuli-specific manner has been reported for the TrxR1 gene (reviewed in (270). Characterization of the promoter region and transcriptional regulation of the GPx4 gene also has been reported (157,219). An interesting, speculative question is whether all or some selenoprotein genes contain potential selenium-response elements.…”

Section: From Selenium To Selenoproteins 783mentioning

confidence: 99%

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2007

Antioxidants & Redox Signaling

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Identification of the Positive Regulatory and Distinct Core Regions of Promoters, and Transcriptional Regulation in Three Types of Mouse Phospholipid Hydroperoxide Glutathione Peroxidase

Cited by 26 publications

References 28 publications

Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

Depletion of Selenoprotein GPx4 in Spermatocytes Causes Male Infertility in Mice

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