Activation of the Ras-ERK pathway inhibits retinoic acid-induced stimulation of tissue transglutaminase expression in NIH3T3 cells.
Retinoic acid (RA) is a potent activator of tissue transglutaminase (TGase) expression, and it was recently shown that phosphoinositide 3-kinase (PI3K) activity was required for RA to increase TGase protein levels. To better understand how RA-mediated TGase expression is regulated, we considered whether co-stimulation of NIH3T3 cells with RA and epidermal growth factor (EGF), a known activator of PI3K, would facilitate the induction or increase the levels of TGase expression. Instead of enhancing these parameters, EGF inhibited RA-induced TGase expression. Activation of the Ras-ERK pathway by EGF was sufficient to elicit this effect, since continuous Ras signaling mimicked the actions of EGF and inhibited RA-induced TGase expression, whereas blocking ERK activity in these same cells restored the ability of RA to up-regulate TGase expression. However, TGase activity is not antagonistic to EGF signaling. The mitogenic and anti-apoptotic effects of EGF were not compromised by TGase overexpression, and in fact, exogenous TGase expression promoted basal cell growth and resistance to serum deprivation-induced apoptosis. Moreover, analysis of TGase expression and GTP binding activity in a number of cell lines revealed high basal TGase GTP binding activity in tumor cell lines U87 and MDAMB231, indicating that constitutively active TGase may be a characteristic of certain cancer cells. These findings demonstrate that TGase may serve as a survival factor and RA-induced TGase expression requires the activation of PI3K but is antagonized by the Ras-ERK pathway.
Antonyak
Marc A
MA
Department of Molecular Medicine, Veterinary Medical College, Cornell University, Ithaca, NY 14853, USA.
McNeill
Conor J
CJ
Wakshlag
Joseph J
JJ
Boehm
Jason E
JE
Cerione
Richard A
RA
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011503:Transglutaminases / Q000096:biosynthesis*; D014212:Tretinoin / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D018631:ras Proteins / Q000502:physiology*
D014212:Tretinoin; D004815:Epidermal Growth Factor; D006160:Guanosine Triphosphate; D011503:Transglutaminases; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D018631:ras Proteins