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Requirement of TGF-beta receptor-dependent activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (Sapks) for TGF-beta up-regulation of the urokinase-type plasminogen activator receptor.
J Cell Physiol. 2004 May; 199(2):284-92.JC

Abstract

We have previously demonstrated that activation of the Ras/Mapk pathways is required for transforming growth factor beta (TGF-beta) induction of TGF-beta(1) expression. Here we examined the role of the Ras/Mapk pathways in TGF-beta induction of urokinase-type plasminogen activator receptor (uPAR) expression in untransformed intestinal epithelial cells (IECs). TGF-beta activated the stress-activated protein kinases (Sapk)/c-Jun N-terminal kinases (JNKs) within 5-10 min, an effect that preceeded TGF-beta induction of uPAR expression in these cells. TGF-beta induction of both JNK1 activity and JunD phosphorylation was blocked by expression of a dominant-negative mutant of the type II TGF-beta receptor (DN TbetaRII), a dominant-negative mutant of MKK4 (DN MKK4), or a dominant-negative mutant of Ras (RasN17), or by the addition of the JNK inhibitor SP600125. TGF-beta also induced AP-1 complex formation at the distal AP-1 site (-184 to -178) of the uPAR promoter within 2 h of TGF-beta addition, consistent with the time-dependent up-regulation of uPAR expression. The primary components present in the TGF-beta-stimulated AP-1 complex bound to the uPAR promoter were Jun D and Fra-2. Moreover, addition of SP600125, or expression of DN MKK4 or DN TbetaRII, blocked TGF-beta up-regulation of uPAR in IECs. Accordingly, our results indicate that TGF-beta activates the Ras/MKK4/JNK1 signaling cascade, leading to induction of AP-1 activity, which, in turn, up-regulates uPAR expression. Our results also indicate that the type II TGF-beta receptor (RII) is required for TGF-beta activation of JNK1 and the resulting up-regulation of uPAR expression.

Authors+Show Affiliations

Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey 17033, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15040011

Citation

Yue, Jianbo, et al. "Requirement of TGF-beta Receptor-dependent Activation of c-Jun N-terminal Kinases (JNKs)/stress-activated Protein Kinases (Sapks) for TGF-beta Up-regulation of the Urokinase-type Plasminogen Activator Receptor." Journal of Cellular Physiology, vol. 199, no. 2, 2004, pp. 284-92.
Yue J, Sun B, Liu G, et al. Requirement of TGF-beta receptor-dependent activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (Sapks) for TGF-beta up-regulation of the urokinase-type plasminogen activator receptor. J Cell Physiol. 2004;199(2):284-92.
Yue, J., Sun, B., Liu, G., & Mulder, K. M. (2004). Requirement of TGF-beta receptor-dependent activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (Sapks) for TGF-beta up-regulation of the urokinase-type plasminogen activator receptor. Journal of Cellular Physiology, 199(2), 284-92.
Yue J, et al. Requirement of TGF-beta Receptor-dependent Activation of c-Jun N-terminal Kinases (JNKs)/stress-activated Protein Kinases (Sapks) for TGF-beta Up-regulation of the Urokinase-type Plasminogen Activator Receptor. J Cell Physiol. 2004;199(2):284-92. PubMed PMID: 15040011.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Requirement of TGF-beta receptor-dependent activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (Sapks) for TGF-beta up-regulation of the urokinase-type plasminogen activator receptor. AU - Yue,Jianbo, AU - Sun,Baodong, AU - Liu,Guangming, AU - Mulder,Kathleen M, PY - 2004/3/25/pubmed PY - 2004/5/27/medline PY - 2004/3/25/entrez SP - 284 EP - 92 JF - Journal of cellular physiology JO - J Cell Physiol VL - 199 IS - 2 N2 - We have previously demonstrated that activation of the Ras/Mapk pathways is required for transforming growth factor beta (TGF-beta) induction of TGF-beta(1) expression. Here we examined the role of the Ras/Mapk pathways in TGF-beta induction of urokinase-type plasminogen activator receptor (uPAR) expression in untransformed intestinal epithelial cells (IECs). TGF-beta activated the stress-activated protein kinases (Sapk)/c-Jun N-terminal kinases (JNKs) within 5-10 min, an effect that preceeded TGF-beta induction of uPAR expression in these cells. TGF-beta induction of both JNK1 activity and JunD phosphorylation was blocked by expression of a dominant-negative mutant of the type II TGF-beta receptor (DN TbetaRII), a dominant-negative mutant of MKK4 (DN MKK4), or a dominant-negative mutant of Ras (RasN17), or by the addition of the JNK inhibitor SP600125. TGF-beta also induced AP-1 complex formation at the distal AP-1 site (-184 to -178) of the uPAR promoter within 2 h of TGF-beta addition, consistent with the time-dependent up-regulation of uPAR expression. The primary components present in the TGF-beta-stimulated AP-1 complex bound to the uPAR promoter were Jun D and Fra-2. Moreover, addition of SP600125, or expression of DN MKK4 or DN TbetaRII, blocked TGF-beta up-regulation of uPAR in IECs. Accordingly, our results indicate that TGF-beta activates the Ras/MKK4/JNK1 signaling cascade, leading to induction of AP-1 activity, which, in turn, up-regulates uPAR expression. Our results also indicate that the type II TGF-beta receptor (RII) is required for TGF-beta activation of JNK1 and the resulting up-regulation of uPAR expression. SN - 0021-9541 UR - https://www.unboundmedicine.com/medline/citation/15040011/Requirement_of_TGF_beta_receptor_dependent_activation_of_c_Jun_N_terminal_kinases__JNKs_/stress_activated_protein_kinases__Sapks__for_TGF_beta_up_regulation_of_the_urokinase_type_plasminogen_activator_receptor_ L2 - https://doi.org/10.1002/jcp.10469 DB - PRIME DP - Unbound Medicine ER -