Expression of a Novel, Sterol-Insensitive Form of Sterol Regulatory Element Binding Protein 2 (SREBP2) in Male Germ Cells Suggests Important Cell- and Stage-Specific Functions for SREBP Targets during Spermatogenesis

Wang, Hang; Liu, Feng; Millette, Clarke F.; Kilpatrick, Daniel L.

doi:10.1128/mcb.22.24.8478-8490.2002

Cited by 29 publications

(30 citation statements)

References 61 publications

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“…Sterols regulate this processing step as part of a homeostatic, inhibitory feedback mechanism by blocking the transport of the SREBP precursor from the endoplasmic reticulum to the Golgi apparatus (19). In contrast to this, translation of the alternatively spliced SREBP2gc mRNA generates a soluble, constitutively active transcription factor that consequently is insensitive to cholesterol feedback control (50). These observations suggested that SREBP2gc performs novel functions during spermatogenesis, not restricted to cholesterol metabolism alone.…”

mentioning

confidence: 64%

“…Due to SREBP2gc's unique structure, SREBP2gc protein levels in spermatogenic cells are unaffected by sterol concentrations that suppress formation of transcriptionally active SREBPs in somatic cells by feedback inhibition of precursor processing (50). Thus, we examined whether SREBP2 protein levels were affected by sterols in GC-4spc cells.…”

Section: Resultsmentioning

confidence: 99%

“…The oligodeoxynucleotides used for generating various DNA probes and competitors for electrophoretic mobility shift assays (EMSAs) as well as primers for RT-PCR are available upon request. EMSAs were performed using nuclear extracts and an SRE-1 probe, as in previous studies of SREBP2gc (50).…”

Section: Methodsmentioning

confidence: 99%

“…Total RNAs were prepared and analyzed by Northern analysis and reverse transcription-PCR (RT-PCR) as previously described (50). A 1.8-kb rat SREBP2gc cDNA was used as the probe for Northern analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, nothing is currently known about the cell-specific regulators of gene promoters expressed in spermatocytes. Sterol response element binding protein 2gc (SREBP2gc) is a 55-kDa, germ cell-enriched form of the basic helix-loop-helix leucine zipper (bHLHZip) transcription factor SREBP2 (50). Its expression is highly up-regulated during late meiosis and in early-round spermatids, suggesting stage-specific functions.…”

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confidence: 99%

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Novel Role for a Sterol Response Element Binding Protein in Directing Spermatogenic Cell-Specific Gene Expression

Wang¹,

Agustin

Witman

et al. 2004

Molecular and Cellular Biology

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Sperm are highly specialized cells, and their formation requires the synthesis of a large number of unique mRNAs. However, little is known about the transcriptional mechanisms that direct male germ cell differentiation. Sterol response element binding protein 2gc (SREBP2gc) is a spermatogenic cell-enriched isoform of the ubiquitous transcription factor SREBP2, which in somatic cells is required for homeostatic regulation of cholesterol. SREBP2gc is selectively enriched in spermatocytes and spermatids, and, due to its novel structure, its synthesis is not subject to cholesterol feedback control. This suggested that SREBP2gc has unique cell-and stage-specific functions during spermatogenesis. Here, we demonstrate that this factor activates the promoter for the spermatogenesis-related gene proacrosin in a cell-specific manner. Multiple SREBP2gc response elements were identified within the 5-flanking and proximal promoter regions of the proacrosin promoter. Mutating these elements greatly diminished in vivo expression of this promoter in spermatogenic cells of transgenic mice. These studies define a totally new function for an SREBP as a transactivator of male germ cell-specific gene expression. We propose that SREBP2gc is part of a cadre of spermatogenic cell-enriched isoforms of ubiquitously expressed transcriptional coregulators that were specifically adapted in concert to direct differentiation of the male germ cell lineage.Sperm are highly differentiated cells that are uniquely adapted to their function as motile cells mediating fertilization. As such, they serve as an important model for exploring regulatory programs responsible for cellular differentiation (17). Spermatogenesis consists of a complex interplay between cellspecific gene transcription, RNA processing, and translational regulation (8,17). It occurs in a series of proliferation and differentiation stages, which can be subdivided into mitotic, meiotic, and spermiogenic phases. Each phase is characterized by distinct cell types, namely, spermatogonia, spermatocytes, and spermatids, respectively. The highly specialized nature of sperm is reflected in the large number of cell-specific transcripts and proteins they express (8), many of which are associated with unique sperm structures such as the acrosome, sperm tail, and the highly compacted sperm chromosomal DNA. Unique proteins also are required to meet specialized requirements for energy metabolism, meiosis, and the maturation of haploid cells, including cell-specific proteins that compensate for X chromosome inactivation (e.g., phosphoglycerate kinase 2 [pgk-2]) (9). These various gene products also must be expressed at the appropriate time to ensure normal development. Thus, sperm formation requires both the generation of a large number of cell-specific gene products and the coordination of this differentiation program in a stepwise, stage-appropriate manner. A key question is the nature of the transcriptional network that controls the elaboration of this program.Cell-specific transcription from ...

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mentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Novel Role for a Sterol Response Element Binding Protein in Directing Spermatogenic Cell-Specific Gene Expression

Wang¹,

Agustin

Witman

et al. 2004

Molecular and Cellular Biology

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Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: Intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage‐gated channels, methylation/acetylation, and transcription factors

Hermo

Pelletier

Cyr

et al. 2009

Microscopy Res & Technique

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As germ cells divide and differentiate from spermatogonia to spermatozoa, they share a number of structural and functional features that are common to all generations of germ cells and these features are discussed herein. Germ cells are linked to one another by large intercellular bridges which serve to move molecules and even large organelles from the cytoplasm of one cell to another. Mitochondria take on different shapes and features and topographical arrangements to accommodate their specific needs during spermatogenesis. The nuclear envelope and pore complex also undergo extensive modifications concomitant with the development of germ cell generations. Apoptosis is an event that is normally triggered by germ cells and involves many proteins. It occurs to limit the germ cell pool and acts as a quality control mechanism. The ubiquitin pathway comprises enzymes that ubiquitinate as well as deubiquitinate target proteins and this pathway is present and functional in germ cells. Germ cells express many proteins involved in water balance and pH control as well as voltage-gated ion channel movement. In the nucleus, proteins undergo epigenetic modifications which include methylation, acetylation, and phosphorylation, with each of these modifications signaling changes in chromatin structure. Germ cells contain specialized transcription complexes that coordinate the differentiation program of spermatogenesis, and there are many male germ cell-specific differences in the components of this machinery. All of the above features of germ cells will be discussed along with the specific proteins/genes and abnormalities to fertility related to each topic.

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Specificity of Retinol, Estrogen and Steroid Linked Proteins

Gupta

2005

Proteomics of Spermatogenesis

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Retinoids and estrogens are small lipophilic compounds, which play important roles in verteberate development, reproduction and homeostasis. Both ligands are activators of their own receptors, which belong to nuclear superfamily and act as transcription factors. The requirement of vitamin A in spermatogenesis became clear from vitamin A deficient (VAD) mice, which showed the presence of only Sertoli cells and undifferentiated A spermatogonia in testis, with loss of subsequent stages of spermatgenesis. Vitamin A deficient mice showed germ cell arrest at the end of S phase of cell cycle. H1 histone kinase, the marker of M phase, is decreased in vitamin A deficient testis but restored or increased following retinol treatment (Wang and Kim, 1993). Retinoic acid receptors have been identified in testis germ cells by many investigators. In part of this section, our main concern would be to describe the characteristic features of the retinol binding proteins (the transport proteins of retinol), specific enzymes involved in retinol metabolism, the retinol receptors and their nuclear receptor homologues found in testis as orphan receptors. The molecules that received considerable attention during recent years, comprise derivatives of vitamin A (retinol) called retinoids. Retinol is converted to active metabolites including all-trans-retinoic acid (RA) through multiple metabolic pathways. Retinoids are important molecules whose action is mediated through receptors during development and differentiation. Retinol Binding ProteinsAs hydrophobic nutrients, retinoids and fatty acids exist in aqueous environments bound to specific carrier proteins. These proteins belong to a superfamily of cellular lipophilic transport proteins that are believed to be involved in the uptake, transport, and metabolism of their ligands. This superfamily includes retinoid-bindii protein Emily, the fatty acid binding protein family, adipocyte lipid binding protein and myelin P2. These proteins are small (14-15kDa) in molecular size and have high degree of sequence conservation across species. They have strikingly similar tertiary structures and many physical characteristics in common.Cellular retinol-binding protein (CRBP) has been known in testis and epididymis since long. The CRBP was found in the seminiferous tubules, with a striking localization within Sertoli cells. A distinct cyclic variation of specific staining for CRBP within Sertoli cells is observed during the spermatogenic cycle. Within the epididymis CRBP is selectively localized

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Expression of a Novel, Sterol-Insensitive Form of Sterol Regulatory Element Binding Protein 2 (SREBP2) in Male Germ Cells Suggests Important Cell- and Stage-Specific Functions for SREBP Targets during Spermatogenesis

Cited by 29 publications

References 61 publications

Novel Role for a Sterol Response Element Binding Protein in Directing Spermatogenic Cell-Specific Gene Expression

Novel Role for a Sterol Response Element Binding Protein in Directing Spermatogenic Cell-Specific Gene Expression

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: Intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage‐gated channels, methylation/acetylation, and transcription factors

Specificity of Retinol, Estrogen and Steroid Linked Proteins

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