TY - JOUR
T1 - Deregulation of the signaling pathways controlling urokinase production
T2 - Its relationship with the invasive phenotype
AU - Aguirre Ghiso, Julio A.
AU - Alonso, Daniel F.
AU - Farias, Eduardo F.
AU - Gomez, Daniel E.
AU - Bal De Kier Joffè, Elisa
PY - 1999/7/15
Y1 - 1999/7/15
N2 - We review the evidence in support of the notion that, upon experimental oncogenic transformation or in spontaneous human cancers, mitogenesis and expression of urokinase (uPA) and its receptor (uPAR) are activated through common signaling complexes and pathways. It is well documented that uPA, uPAR or metalloproteinases (MMPs) are overexpressed in tumor cells of mesenchymal or epithelial origin and these molecules are required for tumor invasion and metastasis. Furthermore, oncogenic stimuli, which may render the transformed cells tumorigenic and metastatic in vivo, activate, in a constitutive fashion, the extracellular-regulated kinases (Erk 1 and 2) classical mitogenic pathway and others such as the NH2-Jun-kinase (Jnk). Cells from human tumors or oncogene-transformed cells overexpress uPA and uPAR, and also show a sustained activation of the above-mentioned signaling modules. In this paper we show that the classical mitogenic pathway involving Ras-Erk, PKC- Erk or Rac-JNK, among others, is activated by growth factors or endogenously by oncogenes, and constitutively activates uPA and uPAR expression. All the data obtained from human tumors or experimental systems, incorporated into a general model, indicate that oncogenic stimuli lead to the constitutive activation of mitogenesis and uPA and its receptor expression, through the activation of the same classical and nonclassical signaling complexes and pathways that regulate cell proliferation. We also discuss contrasting points of view. For instance, what governs the differential regulation of mitogenesis and the signal that leads to protease overexpression in a way that allows normal cells during physiological events to respond to growth factors, and proliferate without overexpressing extracellular matrix (ECM) proteases? Or how can cells remodel their microenvironment without proliferating? What restrains benign tumors from overexpressing tumor- associated proteases when they certainly have the mitogenic signal fully activated? This may occur by the differential regulation of transcriptional programs and recent reports reviewed in this paper may provide an insight into how this occurs at the signaling and transcriptional levels.
AB - We review the evidence in support of the notion that, upon experimental oncogenic transformation or in spontaneous human cancers, mitogenesis and expression of urokinase (uPA) and its receptor (uPAR) are activated through common signaling complexes and pathways. It is well documented that uPA, uPAR or metalloproteinases (MMPs) are overexpressed in tumor cells of mesenchymal or epithelial origin and these molecules are required for tumor invasion and metastasis. Furthermore, oncogenic stimuli, which may render the transformed cells tumorigenic and metastatic in vivo, activate, in a constitutive fashion, the extracellular-regulated kinases (Erk 1 and 2) classical mitogenic pathway and others such as the NH2-Jun-kinase (Jnk). Cells from human tumors or oncogene-transformed cells overexpress uPA and uPAR, and also show a sustained activation of the above-mentioned signaling modules. In this paper we show that the classical mitogenic pathway involving Ras-Erk, PKC- Erk or Rac-JNK, among others, is activated by growth factors or endogenously by oncogenes, and constitutively activates uPA and uPAR expression. All the data obtained from human tumors or experimental systems, incorporated into a general model, indicate that oncogenic stimuli lead to the constitutive activation of mitogenesis and uPA and its receptor expression, through the activation of the same classical and nonclassical signaling complexes and pathways that regulate cell proliferation. We also discuss contrasting points of view. For instance, what governs the differential regulation of mitogenesis and the signal that leads to protease overexpression in a way that allows normal cells during physiological events to respond to growth factors, and proliferate without overexpressing extracellular matrix (ECM) proteases? Or how can cells remodel their microenvironment without proliferating? What restrains benign tumors from overexpressing tumor- associated proteases when they certainly have the mitogenic signal fully activated? This may occur by the differential regulation of transcriptional programs and recent reports reviewed in this paper may provide an insight into how this occurs at the signaling and transcriptional levels.
KW - Intracellular signaling
KW - Invasion
KW - Mitogenesis
KW - Oncogenes
KW - Proteases
KW - Transformation
KW - Tumorigenes is
KW - UPA
KW - UPAR
UR - http://www.scopus.com/inward/record.url?scp=0033565976&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033565976&partnerID=8YFLogxK
U2 - 10.1046/j.1432-1327.1999.00507.x
DO - 10.1046/j.1432-1327.1999.00507.x
M3 - Review article
C2 - 10406935
AN - SCOPUS:0033565976
SN - 0014-2956
VL - 263
SP - 295
EP - 304
JO - European Journal of Biochemistry
JF - European Journal of Biochemistry
IS - 2
ER -