p21 expression is induced by activation of nuclear nerve growth factor-induced Balpha (Nur77) in pancreatic cancer cells.

Abstract

1,1-Bis(3'-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH3) activates the orphan receptor nerve growth factor-induced Balpha (Nur77) in cancer cells, and in this study, DIM-C-pPhOCH3 decreased Panc1 pancreatic cancer cell survival and arrested cells in G0-G1. These responses were accompanied by induction of the cyclin-dependent kinase inhibitor p21 in pancreatic cancer cells. Mechanistic studies showed that induction of p21 mRNA and protein by DIM-C-pPhOCH3 was Nur77 dependent but did not depend on Krüppel-like factor 4, which was also induced by DIM-C-pPhOCH3. Activation of p21 promoter constructs by DIM-C-pPhOCH3 required the GC-rich proximal region of the promoter, and results of RNA interference studies showed that Nur77-dependent activation of the p21 promoter involved interactions with Sp1 and Sp4 but not Sp3. Interactions of Nur77 with the p21 promoter in Panc1 cells treated with DIM-C-pPhOCH3 were also confirmed in chromatin immunoprecipitation assays. These data show that activation of nuclear Nur77 results in a novel pathway for induction of p21, which is independent of Nur77 response elements but dependent on Sp proteins bound to the GC-rich proximal region of the p21 promoter.

• Authors: Syng-Ook Lee, Sudhakar Chintharlapalli, Shengxi Liu, Sabitha Papineni, Sung Dae Cho, Kyungsil Yoon, Stephen Safe
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 7 Issue 7 Pg. 1169-78 (Jul 2009) ISSN: 1557-3125 [Electronic] United States
• PMID: 19584258 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1,1-bis(3'-indolyl)-1-(p-anisyl)methane
• Anisoles
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Indoles
• Intercalating Agents
• KLF4 protein, human
• Kruppel-Like Factor 4
• NR4A1 protein, human
• Nuclear Receptor Subfamily 4, Group A, Member 1
• DAPI

Topics

• Anisoles (pharmacology)
• Apoptosis (physiology)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis, genetics, metabolism)
• Data Interpretation, Statistical
• Gene Expression Regulation, Neoplastic
• Humans
• Indoles (metabolism, pharmacology)
• Intercalating Agents (metabolism)
• Kruppel-Like Factor 4
• Nuclear Receptor Subfamily 4, Group A, Member 1 (biosynthesis, genetics, metabolism)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Promoter Regions, Genetic