Abstract
The osteogenic growth peptide (OGP) is an extracellular mitogen identical to the histone H4 (H4) COOH-terminal residues 90-103, which regulates osteogenesis and hematopoiesis. By Northern analysis, OGP mRNA is indistinguishable from H4 mRNA. Indeed, cells transfected with a construct encoding [His102]H4 secreted the corresponding [His13]OGP. These results suggest production of OGP from H4 genes. Cells transfected with H4-chloramphenicol acetyltransferase (CAT) fusion genes expressed both "long" and "short" CAT proteins. The short CAT was retained following an ATG --> TTG mutation of the H4 ATG initiation codon, but not following mutation of the in-frame internal ATG85 codon, which, unlike ATG1, resides within a perfect context for translational initiation. These results suggest that a PreOGP is translated starting at AUG85. The translational initiation at AUG85 could be inhibited by optimizing the nucleotide sequence surrounding ATG1 to maximally support upstream translational initiation, thus implicating leaky ribosomal scanning in usage of the internal AUG. Conversion of the predicted PreOGP to OGP was shown in a cell lysate system using synthetic [His102]H4-(85-103) as substrate. Together, our results demonstrate that H4 gene expression diverges at the translational level into the simultaneous parallel production of both H4, a nuclear structural protein, and OGP, an extracellular regulatory peptide.
Highlights
The osteogenic growth peptide (OGP) is an extracellular mitogen identical to the histone H4 (H4) COOHterminal residues 90 –103, which regulates osteogenesis and hematopoiesis
We demonstrate that histone H4 genes do encode OGP, and that OGP synthesis is supported by leaky ribosomal scanning through the suboptimal AUG initiator of histone H4 mRNA
Histone H4 Gene Expresses OGP— OGP, present abundantly in the serum and in cell culture media, is identical to the H4 carboxyl terminus, it was not known whether the two polypeptides, H4 and OGP, could be synthesized from the same template
Summary
The osteogenic growth peptide (OGP) is an extracellular mitogen identical to the histone H4 (H4) COOHterminal residues 90 –103, which regulates osteogenesis and hematopoiesis. Cells transfected with a construct encoding [His102]H4 secreted the corresponding [His13]OGP. These results suggest production of OGP from H4 genes. The short CAT was retained following an ATG 3 TTG mutation of the H4 ATG initiation codon, but not following mutation of the in-frame internal ATG85 codon, which, unlike ATG1, resides within a perfect context for translational initiation These results suggest that a PreOGP is translated starting at AUG85. The osteogenic growth peptide (OGP), initially isolated from regenerating bone marrow, is identical to the carboxyl-terminal residues 90 –103 of histone H4 We demonstrate that histone H4 genes do encode OGP, and that OGP synthesis is supported by leaky ribosomal scanning through the suboptimal AUG initiator of histone H4 mRNA
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