scholarly journals Epidermal growth factor-stimulated parathyroid hormone-related protein expression involves increased gene transcription and mRNA stability

1995 ◽  
Vol 307 (1) ◽  
pp. 159-167 ◽  
Author(s):  
J K Heath ◽  
J Southby ◽  
S Fukumoto ◽  
L M O'Keeffe ◽  
T J Martin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parathyroid Hormone ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Gene Transcription ◽  
Mrna Stability ◽  
Specific Effect ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Epidermal Growth

Epidermal growth factor (EGF) produced rapid and striking effects on parathyroid hormone-related protein (PTHrP) gene expression in the immortalized human keratinocyte cell line, HaCaT. Steady-state levels of PTHrP mRNA and secreted PTHrP were increased 10-fold by maximally effective concentrations of EGF. EGF increased both PTHrP gene transcription and PTHrP mRNA stability. Nuclear run-on assays demonstrated a 4-fold increase in transcriptional rate in EGF-stimulated cells while transient transfection analysis indicated that the action of EGF on transcription involved both the GC-rich promoter, P2, and the downstream TATA promoter, P3, but apparently not the upstream TATA promoter, P1. In experiments where EGF treatment produced more stable PTHrP transcripts, the half-life of c-fos mRNA was unaltered, suggesting a relatively specific effect of EGF. Moreover, only those species of PTHrP mRNA containing two of the alternative 3′ exons (exons VII and VIII) were stable, those containing exon IX were not. Reverse-transcription PCR demonstrated that EGF produced differential increases in the abundance of PTHrP mRNA species initiated by the three PTHrP promoters. The major effect was seen on the abundance of transcripts initiated by P1 and P2, with less marked regulation of P3-initiated transcripts. Thus EGF regulation of PTHrP gene expression in HaCaT cells is multifactorial and the combination of its actions at the 5′ and 3′ ends of the gene favours the accumulation of subpopulations of PTHrP mRNA containing exons I, VII and VIII.

scholarly journals Regulation of parathyroid hormone-related protein gene expression by epidermal growth factor-family ligands in primary human keratinocytes

2004 ◽  
Vol 181 (1) ◽  
pp. 179-190 ◽  
Author(s):  
YM Cho ◽  
DA Lewis ◽  
PF Koltz ◽  
V Richard ◽  
TA Gocken ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Reporter Gene ◽  
Human Keratinocytes ◽  
Mrna Levels ◽  
Related Protein ◽  
Primary Keratinocytes ◽  
Primary Human Keratinocytes ◽  
Parathyroid Hormone Related Protein ◽  
Epidermal Growth

Cultured primary human keratinocytes were the first non-cancer-derived cell type reported to produce the humoral hypercalcemia factor, parathyroid hormone-related protein (PTHrP). Emerging evidence suggests that only a subset of keratinocytes produce high levels of PTHrP in vivo. We found that the PTHrP mRNA content of intact human skin was minimal, whereas transcripts were easily detectable in primary keratinocytes derived from those skin samples. We hypothesized that conditions associated with growth in culture activated PTHrP gene expression in primary keratinocytes. In culture, keratinocytes produce a number of epidermal growth factor (EGF)-like ligands (transforming growth factor-alpha, heparin binding-EGF and amphiregulin) and their receptor, ErbB1. Treatment of keratinocytes with a specific erbB1 inhibitor (PD153035) reduced PTHrP mRNA levels by >80% in rapidly growing keratinocytes. Treatment of keratinocytes with reagents that neutralize amphiregulin reduced PTHrP mRNA levels by approximately 60%. Blockade of erbB1 signaling reduces transcription from the endogenous PTHrP P3-TATA promoter. The Ets transcription factor-binding site, 40 bases upstream of the P3 promoter, is required for baseline expression of PTHrP reporter gene constructs in keratinocytes; in addition, cotransfection of Ets-1 and Ets-2 expression vectors activate the reporter gene constructs. Finally, disruption of both ras and raf signaling reduce reporter gene expression by 80%, suggesting that ErbB1 signaling is mediated by the classic ras/MAP kinase pathway. These findings suggest that acquisition of EGF-like ligand expression has the potential to substantially activate PTHrP gene expression in the epidermis.

scholarly journals Rapid phosphorylation of Ets-2 accompanies mitogen-activated protein kinase activation and the induction of heparin-binding epidermal growth factor gene expression by oncogenic Raf-1.

1997 ◽  
Vol 17 (5) ◽  
pp. 2401-2412 ◽  
Author(s):  
S A McCarthy ◽  
D Chen ◽  
B S Yang ◽  
J J Garcia Ramirez ◽  
H Cherwinski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Map Kinase ◽  
Gene Transcription ◽  
Map Kinases ◽  
Heparin Binding ◽  
Promoter Activation ◽  
Mitogen Activated Protein ◽  
Epidermal Growth

Heparin-binding epidermal growth factor (HB-EGF) gene transcription is rapidly activated in NIH 3T3 cells transformed by oncogenic Ras and Raf and mediates the autocrine activation of the c-Jun N-terminal kinases (JNKs) observed in these cells. A 1.7-kb fragment of the promoter of the murine HB-EGF gene linked to a luciferase reporter was strongly induced following activation of deltaRaf-1:ER, a conditionally active form of oncogenic human Raf-1. Promoter activation by deltaRaf-1:ER required a composite AP-1/Ets transcription factor binding site located between bp -974 and -988 upstream of the translation initiation site. In vivo genomic footprinting indicated that the basal level of occupancy of this composite AP-1/Ets element increased following deltaRaf-1:ER activation. Cotransfection of Ets-2 and p44 mitogen-activated protein (MAP) kinase expression vectors strongly potentiated HB-EGF promoter activation in response to deltaRaf-1:ER. Potentiated activation required both p44 MAP kinase catalytic activity and threonine 72 in the Pointed domain of Ets-2. Biochemical assays demonstrated the ability of the p42 and p44 MAP kinases to phosphorylate Ets-2 on threonine 72. Importantly, in intact cells, the kinetics of phosphorylation of Ets-2 on this residue closely mirror the activation of the p42 and p44 MAP kinases and the observed onset of HB-EGF gene transcription following deltaRaf-1:ER activation. These data firmly establish Ets-2 as a direct target of the Raf-MEK-MAP kinase signaling pathway and strongly implicate Ets-2 in the regulation of HB-EGF gene expression.

Ets-1 activates parathyroid hormone-related protein gene expression in tumorigenic breast epithelial cells

2003 ◽  
Vol 204 (1-2) ◽  
pp. 155-168 ◽  
Author(s):  
Christophe Cataisson ◽  
Johnthan Gordon ◽  
Mickael Roussière ◽  
Arman Abdalkhani ◽  
Ralph Lindemannn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parathyroid Hormone ◽  
Epithelial Cells ◽  
Protein Gene ◽  
Related Protein ◽  
Breast Epithelial Cells ◽  
Parathyroid Hormone Related Protein ◽  
Breast Epithelial

The epidermal growth factor receptor ligand amphiregulin is a negative regulator of hepatic acute-phase gene expression

2009 ◽  
Vol 51 (6) ◽  
pp. 1010-1020 ◽  
Author(s):  
Ana Pardo-Saganta ◽  
Maria Ujue Latasa ◽  
Josefa Castillo ◽  
Laura Alvarez-Asiain ◽  
María J. Perugorría ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Acute Phase ◽  
Growth Factor Receptor ◽  
Negative Regulator ◽  
Receptor Ligand ◽  
Epidermal Growth
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