JunB is a repressor of MMP-9 transcription in depolarized rat brain neurons

Rylski, Marcin; Amborska, Renata; Zybura, Katarzyna; Michaluk, Piotr; Bielińska, Beata; Konopacki, Filip A.; Wilczyński, Grzegorz M.; Kaczmarek, Leszek

doi:10.1016/j.mcn.2008.09.005

Cited by 37 publications

(38 citation statements)

References 86 publications

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“…Although these different scenarios require further study, the required role of the c-Jun binding activity in p38␥ stimulating c-Jun synthesis, MMP9 transcription, and invasion highlights an essential role of this protein-complex in triggering the invasion cascade. c-Jun was previously shown to bind the MMP9 promoter in cardiac (50) but not in neuronal cells (51), and similarly we showed that c-Jun only binds the MMP9 in the presence of p38␥, indicating a determinant role of c-Jun cofactor abundances in its trans-activation of MMP9. Our results suggest that p38␥ may be one of these critical cofactors to determine c-Jun transcriptional activity by increasing its expression and facilitating its target gene promoter binding.…”

Section: P38␥ Stimulates C-jun and Mmp9 Transcriptionsupporting

confidence: 81%

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

Loesch

Zhi

Hou

et al. 2010

Journal of Biological Chemistry

106

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Mitogen-activated protein kinases (MAPKs) regulate gene expression through transcription factors. However, the precise mechanisms in this critical signal event are largely unknown. Here, we show that the transcription factor c-Jun is activated by p38␥ MAPK, and the activated c-Jun then recruits p38␥ as a cofactor into the matrix metalloproteinase 9 (MMP9) promoter to induce its trans-activation and cell invasion. This signaling event was initiated by hyperexpressed p38␥ that led to increased c-Jun synthesis, MMP9 transcription, and MMP9-dependent invasion through p38␥ interacting with c-Jun. p38␥ requires phosphorylation and its C terminus to bind c-Jun, whereas both c-Jun and p38␥ are required for the trans-activation of MMP9. The active p38␥/c-Jun/MMP9 pathway also exists in human colon cancer, and there is a coupling of increased p38␥ and MMP9 expression in the primary tissues. These results reveal a new paradigm in which a MAPK acts both as an activator and a cofactor of a transcription factor to regulate gene expression leading to an invasive response. MAPKs3 (including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38s) are critical signaling cascades that convert upstream signals into biological responses such as cell proliferation, invasion, and transformation (1). MAPKs are believed to do so by phosphorylating and activating a group of transcription factors, which through binding regulatory DNA elements lead to altered gene transcription. c-Jun is a major component of the AP-1 transcription factor downstream of MAPKs, whereas AP-1 is composed of homodimers of the Jun family or its heterodimers with another transcription factor such as c-Fos to bind the consensus DNA elements TGAg/cTCA (2). c-Jun is activated by JNK through phosphorylation at Ser-63, Ser-73, Thr-91, and Thr-93, and by ERK and p38 via increased gene expression. Activated c-Jun/ AP-1 leads to a cell type-specific biological response through integrated gene expression (1). However, the exact mechanism by which c-Jun converts a MAPK activity into a target gene expression remains mostly unknown.p38 MAPKs consist of four family members (␣, ␤, ␥, and ␦) in which p38␣ is ubiquitously present, whereas p38␥ is highly expressed in certain cancers (3). In addition to well established regulatory effects in cytokine signaling and stress response, substantial evidence suggests that the p38␣ pathway functions as a tumor suppressor (4 -8). p38␥, on the other hand, is a 43-kDa protein with an unique C-terminal motif, KETXL, that can dock with the PDZ (PSD-95/Dlg/ZO-1 homology) domain of other proteins (9, 10). In contrast to p38␣, our recent studies showed that p38␥ is induced by Ras and required for Ras transformation and invasion (11, 12), indicating its oncogenic activity. The underlying mechanisms for p38␥ involvement in Ras tumorigenesis, however, have not been established. In this report, we show that p38␥ acts both as an activator and a cofactor for c-Jun in trans-activating MMP9, a critical matrix metalloprote...

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Section: P38␥ Stimulates C-jun and Mmp9 Transcriptionsupporting

confidence: 81%

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

Loesch

Zhi

Hou

et al. 2010

Journal of Biological Chemistry

106

View full text Add to dashboard Cite

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“…A previous study revealed that MMP-9 mRNA levels increased in response to neuronal depolarization in the rat hippocampus (Rylski et al, 2009). After seizure in kainic acid-treated rats, MMP-9 mRNA is transported to dendrites and synapses in the hippocampal DG .…”

Section: Discussionmentioning

confidence: 86%

“…On the other hand, some of our findings are not consistent with previous reports. For instance, a prominent increase in MMP-9 mRNA levels was observed in rats 2 h after a single 50 mg/kg PTZ dose (Rylski et al, 2009), and MMP-9 activity increased as early as 5 min after bicuculline treatment in mouse cortical cultures (Michaluk et al, 2007). More detailed examination of temporal changes and species differences in MMP-9 expression after single and repeated PTZ injection may help explain these discrepant results.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus

Mizoguchi¹,

Nakade²,

Terabe³

et al. 2011

J. Neurosci.

172

142

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(Ϫ/Ϫ) mice compared with wild-type mice, an observation that was accompanied by decreased hippocampal levels of mature brain-derived neurotrophic factor. Microinjecting the BDNF scavenger TrkB-Fc into the right ventricle before each PTZ treatment significantly suppressed the development of kindling in wild-type mice, whereas no effect was observed in MMP-9 (Ϫ/Ϫ) mice. On the other hand, bilateral injections of pro-BDNF into the hippocampal dentate gyrus significantly enhanced kindling in wild-type mice but not MMP-9 (Ϫ/Ϫ) mice. These findings suggest that MMP-9 is involved in the progression of behavioral phenotypes in kindled mice because of conversion of pro-BDNF to mature BDNF in the hippocampus.

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“…Among the genes only downregulated in group C meningiomas compared to group A, 4 (JUNB, FSTL1, TGFBR3 and MADH7) involved in the transforming growth factor-ß signalling pathway have been previously shown to be downregulated in malignant meningiomas (13). The decreased expression of the protooncogene JUNB, a cell proliferation inhibitor and a repressor of MMP9, might explain the upregulation of MMP9 observed in high-grade meningiomas (56). Furthermore, Slit-2 has been described as a tumour suppressor gene because it is frequently inactivated in various cancers due to hypermethylation of its promoter region (57).…”

Section: ------------------------------------------------------------mentioning

confidence: 97%

Microarray gene expression profiling in meningiomas: Differential expression according to grade or histopathological subtype

Fèvre-Montange¹

2009

Int J Oncol

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JunB is a repressor of MMP-9 transcription in depolarized rat brain neurons

Cited by 37 publications

References 86 publications

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus

Microarray gene expression profiling in meningiomas: Differential expression according to grade or histopathological subtype

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