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J. Biol. Chem., Vol. 280, Issue 2, 1103-1111, January 14, 2005

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Cyclin-dependent Kinase 9 Is Required for Tumor Necrosis Factor--stimulated Matrix Metalloproteinase-9 Expression in Human Lung Adenocarcinoma Cells^*

Bin Shan¶, Ying Zhuo, Dawn Chin, Cindy A. Morris||, Gilbert F. Morris**, and Joseph A. Lasky

From the Pulmonary and Critical Care Section, Department of Medicine, ^||Department of Microbiology, ^**Department of Pathology, Tulane Cancer Center, and Program in Lung Biology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112

The proinflammatory cytokine tumor necrosis factor- (TNF-) promotes tumor progression through activation of matrix metalloproteinase (MMP) activity. MMP-9 is a gelatinase secreted by both cancer cells and surrounding stromal cells, and it contributes to TNF--stimulated tumor invasion and metastasis. Cyclin-dependent kinase 9 (CDK9), the catalytic component of positive transcription elongation factor-b, phosphorylates serine 2 residues in the C-terminal domain of RNA polymerase II for productive transcription elongation and is up-regulated upon exposure to various stresses. This study investigated roles of CDK9 in TNF--stimulated MMP-9 expression in human lung adenocarcinoma cells. CDK9 activity was inhibited using three different strategies, including the CDK9 pharmacological inhibitor 5,6-dichloro-1--D-ribofuranosylbenzimidazole (DRB), a dominant-negative CDK9, and a CDK9-specific small interfering RNA. All three approaches reduced TNF--mediated accumulation of MMP-9 in the conditioned media as demonstrated by gelatin zymography. In contrast, transforming growth factor-1-induced accumulation of MMP-2 was unaffected by DRB. Expression of the MMP-9 gene was examined using reverse transcription real time PCR and using a transient transfection assay to evaluate MMP-9 promoter activity. DRB reduced the TNF--induced increase in MMP-9 mRNA levels but did not effect transforming growth factor-1-induced MMP-2 mRNA expression. Consistently DRB and dominant-negative CDK9 completely abrogated TNF--stimulated human MMP-9 promoter activity. TNF- did not regulate expression or localization of CDK9 or its regulatory partner Cyclin T. However, TNF- stimulated CDK9 binding to Cyclin T and MMP-9 gene occupancy by both CDK9 and the serine 2-phosphorylated form of RNA polymerase II. Our findings indicate that CDK9 mediates TNF--induced MMP-9 transcription. Disruption of TNF- signaling using CDK9 inhibitors could serve as a potential therapeutic strategy against tumor invasion and metastasis.

Received for publication, June 7, 2004 , and in revised form, October 25, 2004.

^* This work was supported in part by National Institutes of Health grants. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Partially supported by a matching fund from Tulane Cancer Center.

To whom correspondence should be addressed: Dept. of Medicine, Pulmonary Section, SL-9, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112-2699. Tel.: 504-588-2251; Fax: 504-587-2144; E-mail: jlasky{at}tulane.edu.

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