Regulation Of Platelet-derived Growth Factor Research Articles

Differential expression of the platelet-derived growth factor-A and -B genes during maturation of monocytes to macrophages

1. 1. Regulation of platelet-derived growth factor (PDGF)-A and -B gene expression was studied using resting monocytes, in vitro matured monocytes and alveolar macrophages. 2. 2. Resting monocytes constitutively transcribed both PDGF-A and -B genes. When monocytes matured to macrophages vitro, the transcription rates of both genes increased markedly. 3. 3. Consistent with the transcription rates, resting monocytes constitutively expressed both PDGF-A and -B mRNAs. Interestingly, the PDGF-B mRNA levels increased markedly after the maturation, whereas the PDGF-A mRNA did not change. 4. 4. Alveolar macrophages constitutively transcribed both PDGF-A and -B genes at almost the same rates. However, these cells contained 5-fold more PDGF-B mRNA than PDGF-A mRNA. 5. 5. Immunohistochemical study using anti-PDGF-AA and anti-PDGF-BB antibodies suggested that PDGF-BB homodimers were more abundant than -AA homodimers or -AB heterodimers in aveolar macrophages and in vitro matured monocytes. 6. 6. Together these observations indicate that in vitro matured monocytes and alveolar macrophages preferentially express PDGF-B mRNA and produce PDGF-BB homodimers, despite the equal transcription rates for both PDGF-A and -B genes.

Platelet-derived growth factor regulation of fos stability correlates with growth induction.

A brief exposure of quiescent, density-arrested Balb/c 3T3 fibroblasts to platelet-derived growth factor (PDGF) results in expression of the proto-oncogene c-fos; furthermore, the translation product of c-fos, p55fos, was shown to have increased stability in cells upon continued exposure to PDGF. The induction of competence or growth initiation requires a longer exposure to PDGF than that necessary for the induction of the immediate-early, growth-related genes. The need for the continued presence of PDGF for growth initiation beyond the time required for the induction of immediate-early gene expression may be due, in part, to PDGF-dependent post-translational stabilizations of gene products. We speculate that a PDGF-mediated event increases p55fos stability, resulting in a continued elevated level of Fos protein, which in turn allows a continued Fos-mediated activity required by Balb/c 3T3 cells to become competent to enter the cell cycle.

Recent developments in the structure, function and regulation of platelet-derived growth factor and its receptors

Recent evidence strongly suggests that production of platelet-derived growth factor (PDGF) is regulated by several mechanisms, including noncoordinate expression of the PDGF A- and B-chain genes, alternative transcript splicing, differential mRNA stability, and translational control. Considerable progress has also been made in our understanding of PDGF receptors. Recent studies demonstrate that there are two distinct PDGF receptor genes. PDGF receptors can undergo dimerization and it has been postulated that dimerization can lead to the formation of three different receptor dimers. In addition, it appears that dimerization is required for activation of PDGF receptors and the biological activity of PDGF. Although relatively little is known about the regulation of PDGF receptors, PDGF receptors are known to be down regulated by PDGF, and expression of PDGF receptors begins relatively early during embryogenesis. Furthermore, the binding of PDGF is regulated by cell density. Unexpectedly, recent evidence suggests that PDGF can localize to the nucleus, which suggests an intranuclear function for PDGF may exist. Together, these findings imply a complex and multi-leveled regulatory scheme for controlling the production of PDGF and its receptors.

Distinct pathways mediate transcriptional regulation of platelet-derived growth factor B/c-sis expression.

The biochemical mechanisms responsible for regulating cellular platelet-derived growth factor expression are incompletely understood. Our previous studies have shown that platelet-derived growth factor B/c-sis mRNA levels are induced in human renal microvascular endothelial cells by either thrombin or transforming growth factor (TGF-beta), while exposure to agents which elevate cAMP levels blocks the induction responses. The current studies use combined transcription run-off and message decay rate experiments to show greater than 3-fold increases in rate of transcription after stimulation with either thrombin or TGF-beta. c-sis message has a 70-90-min half-life under basal conditions that is effectively unaltered by thrombin or TGF-beta. Forskolin does not decrease the stability of c-sis mRNA, although it attenuates transcription increases seen with inducing agents. TGF-beta induction of c-sis transcription is mediated independent of the protein kinase C (Ca2+- and phospholipid-dependent enzyme)-mediated responses to phorbol ester, as it remains intact following down-regulation of protein kinase C response; TGF-beta and phorbol elicit additive induction. Inhibitory effects of cAMP upon transcription act distal to early thrombin-receptor-coupled increases in phosphatidylinositol turnover and are capable of turning off TGF-beta-activated transcription after activation has been established. Both inducing and suppressing agents alter endothelial platelet-derived growth factor B/c-sis mRNA expression dominantly through effects upon rates of transcription, cAMP suppression of transcription is dominant, and TGF-beta and phorbol esters mediate induction of transcription through distinct pathways.

Regulated expression of the platelet-derived growth factor A chain gene in microvascular endothelial cells.

Platelet-derived growth factor (PDGF) is composed of homologous polypeptide chains, termed A and B, that are expressed as mitogenically active A-A, B-B, or A-B dimers. Previous work in our laboratory has demonstrated that PDGF B chain mRNA expression is stimulated in microvascular endothelial cells by phorbol esters (PMA), thrombin, and transforming growth factor-beta (TGF-beta) and blocked by agents that elevate cyclic AMP (cAMP). Here we report the first evidence that the expression of A chain mRNA is also regulated in these cells. PDGF A chain mRNA levels were increased 5-25-fold by phorbol esters, thrombin, and TGF-beta. Transcripts of four different sizes were induced. The increase in A chain mRNA stimulated by TGF-beta was more prolonged (peak 4 h, duration 48 h) than the increase stimulated by PMA and thrombin (peak 4 h, duration 8 h). Among the agents known to increase B chain mRNA levels, PMA was most efficacious, followed in decreasing order by thrombin and TGF-beta. However, for A chain mRNA induction by these same agents, the order was reversed; TGF-beta was most efficacious, followed in decreasing order by thrombin and PMA. Agents that elevate cyclic AMP, known to block induction of B chain mRNA, blocked A chain induction by thrombin but had less effect on A chain mRNA induced by TGF-beta. Thus PDGF A chain mRNA levels are regulated by the same agents that regulate B chain mRNA levels in microvascular endothelial cells. While the changes in A chain mRNA are qualitatively similar to the changes in B chain mRNA in microvascular endothelial cells, there are differences in the relative efficacies of these agents in the regulation of PDGF A and B chain genes. These differences suggest that the forms of PDGF produced by endothelial cells depend on the nature of the inducing stimulus.

Differential regulation of platelet-derived growth factor A and B chain messages in microvascular endothelial cells

Differential regulation of platelet-derived growth factor A and B chain messages in microvascular endothelial cells