Embryonic Expression of the Luteinizing Hormone β Gene Appears to Be Coupled to the Transient Appearance of p8, a High Mobility Group-related Transcription Factor

Abstract

A comparison between two pituitary-derived cell lines (␣T3-1 and L␤T2) that represent gonadotropes at early and late stages of development, respectively, was performed to further elucidate the genomic repertoire required for gonadotrope specification and luteinizing hormone ␤ (LH␤) gene expression. One isolated clone that displayed higher expression levels in L␤T2 cells encodes p8, a high mobility group-like protein with mitogenic potential that is up-regulated in response to proapoptotic stimuli and in some developing tissues. To test the functional significance of this factor in developing gonadotropes, a knockdown of p8 in L␤T2 cells was generated. The loss of p8 mRNA correlated with loss of endogenous LH␤ mRNA and the loss of activity of a transfected LH␤ promoter-driven reporter, even upon treatment with gonadotropin-releasing hormone. In addition, expression of p8 mRNA in developing mouse pituitary glands mirrored its expression in the gonadotrope-derived cell lines and coincided with the first detectable appearance of LH␤ mRNA. In contrast, p8 mRNA was undetectable in the pituitary glands of normal adults. Taken together, our data indicate that p8 is a stage-specific component of the gonadotrope transcriptome that may play a functional role in the initiation of LH␤ gene expression during embryonic cellular differentiation.With its ability to stimulate gonadal steroidogenesis and gametogenesis, luteinizing hormone (LH) 1 is essential for normal reproductive function in mammals (1, 2). Luteinizing hormone is a heterodimeric protein composed of an ␣ glycoprotein hormone subunit (␣GSU) common to all members of the glycoprotein family of hormones that is non-covalently linked to a unique LH␤ subunit that confers its biological specificity (1, 2). Biosynthesis of LH depends on the coordinated expression of both the ␣GSU and LH␤ subunit genes. In humans, the single copy ␣GSU gene resides on chromosome 6q12-q21 (Locus ID 1081) while the LH␤ gene resides amid a cluster of six chorionic gonadotropin-␤ genes on chromosome 19q13.32 (Locus ID 1082). In addition to their different locations within the human genome, the pattern of expression of the genes encoding ␣GSU and LH␤ are temporally and spatially distinct.During development ␣GSU is seen throughout Rathke's pouch as early as embryonic day (e) 9.5 in the mouse (3). By later stages of pituitary development and in adult mammals, ␣GSU expression is limited to thyrotropes and gonadotropes (4). Gonadotrope-specific expression of the ␣GSU gene is controlled by an array of regulatory elements, including the pituitary glycoprotein hormone basal element (5, 6), ␣ basal elements (6), gonadotrope-specific element (7), and tandemly repeated cAMP response elements (8 -10), as well as the intricate interplay between their cognate binding proteins (6).In a fashion similar to the ␣GSU promoter, the LH␤ gene is regulated by a combinatorial array of transcription factors and regulatory elements. In this case, however, the elements consist of those that bind early growth response ...

Regulation of apoptosis by the p8/prothymosin α complex

“…Sequence identity of p8 and HMG-I͞Y is only Ϸ35%, but molecular mass, isoelectric points, hydrophilicity plots, and charge distributions along the polypeptides are very similar (5). An architectural role in transcription was proposed for p8 by analogy with HMG-I͞Y, and recent reports are consistent with this hypothesis (6)(7)(8).…”

Localization, developmental regulation and stress induction of p8-L1 and p8-L2 in zebrafish

“…However, given that p8-L1 and p8-L2 decline to relatively low levels compared to p8 during certain developmental stages, p8 may play a more critical role in embryogenesis than either p8-L1 or p8-L2. Similar results have also bee reported in sea urchin and mice [1,7,26,[30][31][32]. Further studies, such as loss-of-function or dominant-negative approaches, are needed further clarify the roles of these genes in zebrafish embryo development.…”

“…Moreover, activation of p8 is not restricted to the pancreatic cells, but can also occur in the liver, kidney, brain, and intestine [18]. As a result, p8 may regulate many cellular functions such as cell growth promotion [1,2] or inhibition [21,22] and promotion of cell apoptosis [21], tumor development and progression [15,[23][24][25], animal embryo development [1,26] and cell defense [27]. However, the role of p8 in each of these processes may depend on the cell type and/or growth conditions [21].…”

p8 Improves Pancreatic Response to Acute Pancreatitis by Enhancing the Expression of the Anti-inflammatory Protein Pancreatitis-associated Protein I

“…Also, p8 is involved in cell cycle regulation as a growth promoter (6,8) or inhibitor (14,15) or as a mediator of apoptosis (14). In addition, p8 is required for endothelin-induced mesangial cell hypertrophy in the diabetic kidney (16), for initiation of LH␤ gene expression (17) and, in D. melanogaster to stop cell growth in response to starvation (18). Finally, a particularly attractive role in the control of tumor progression was proposed for p8 (19,20).…”