In addition to its central role in blood coagulation and hemostasis, human alpha-thrombin is a growth factor for a variety of cell types. We recently demonstrated that interferon-gamma (IFNgamma)-differentiated U937 cells show increased expression of the proteolytically activated receptor for thrombin (PAR-1) relative to undifferentiated U937. In the present study we show that cell proliferation is inhibited in IFNgamma-differentiated cells relative to undifferentiated U937. Addition of thrombin to the differentiated cells, however, overcomes the inhibition and restores the cells to a highly proliferative state. Ribonuclease protection assays indicate that the IFNgamma-induced growth arrest is associated with an increased expression of the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) and downregulation of cyclin D(1). Treatment of cells with thrombin downregulates p21(CIP1/WAF1) expression in these cells and upregulates cyclin D(1) mRNA expression, thus overcoming the differentiation-related effects in a coordinated manner. Treating differentiated cells with the PAR-1 activation peptide, SFLLRN, stimulates proliferation and has effects similar to those of thrombin on expression of p21(CIP1/WAF1). Thus, it appears that these thrombin stimulated proliferative effects are mediated through activation of PAR-1. These results may help explain how thrombin can overcome growth arrest in normal tissue to initiate tissue repair and why thrombin and thrombin-like enzymes may contribute to unrestricted proliferation observed in certain malignancies.

Naldini, A., Carney, D.H., Pucci, A., & Carraro, F. (2002). Human alpha-Thrombin Stimulates Proliferation of Interferon-gamma Differentiated, Growth-Arrested, U937 Cells, Overcoming Differentiation-Related Changes in Expression of p21CIP1/WAF1 and Cyclin D1. JOURNAL OF CELLULAR PHYSIOLOGY, 191(3), 290-297 [10.1002/jcp.10101].

Human alpha-Thrombin Stimulates Proliferation of Interferon-gamma Differentiated, Growth-Arrested, U937 Cells, Overcoming Differentiation-Related Changes in Expression of p21CIP1/WAF1 and Cyclin D1

NALDINI, A.;PUCCI, A.;CARRARO, F.
2002

Abstract

In addition to its central role in blood coagulation and hemostasis, human alpha-thrombin is a growth factor for a variety of cell types. We recently demonstrated that interferon-gamma (IFNgamma)-differentiated U937 cells show increased expression of the proteolytically activated receptor for thrombin (PAR-1) relative to undifferentiated U937. In the present study we show that cell proliferation is inhibited in IFNgamma-differentiated cells relative to undifferentiated U937. Addition of thrombin to the differentiated cells, however, overcomes the inhibition and restores the cells to a highly proliferative state. Ribonuclease protection assays indicate that the IFNgamma-induced growth arrest is associated with an increased expression of the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) and downregulation of cyclin D(1). Treatment of cells with thrombin downregulates p21(CIP1/WAF1) expression in these cells and upregulates cyclin D(1) mRNA expression, thus overcoming the differentiation-related effects in a coordinated manner. Treating differentiated cells with the PAR-1 activation peptide, SFLLRN, stimulates proliferation and has effects similar to those of thrombin on expression of p21(CIP1/WAF1). Thus, it appears that these thrombin stimulated proliferative effects are mediated through activation of PAR-1. These results may help explain how thrombin can overcome growth arrest in normal tissue to initiate tissue repair and why thrombin and thrombin-like enzymes may contribute to unrestricted proliferation observed in certain malignancies.
Naldini, A., Carney, D.H., Pucci, A., & Carraro, F. (2002). Human alpha-Thrombin Stimulates Proliferation of Interferon-gamma Differentiated, Growth-Arrested, U937 Cells, Overcoming Differentiation-Related Changes in Expression of p21CIP1/WAF1 and Cyclin D1. JOURNAL OF CELLULAR PHYSIOLOGY, 191(3), 290-297 [10.1002/jcp.10101].
File in questo prodotto:
File Dimensione Formato  
Human alpha thrombin stimulates proliferation of interferon gamma differentiated growth arrested U937 cells overcoming differentiationrelated changes in expression of.pdf

non disponibili

Tipologia: Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 177.45 kB
Formato Adobe PDF
177.45 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/22558
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo