p21 expression is induced by activation of nuclear nerve growth factor-induced Balpha (Nur77) in pancreatic cancer cells.
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.
Lee
Syng-Ook
SO
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
Chintharlapalli
Sudhakar
S
Liu
Shengxi
S
Papineni
Sabitha
S
Cho
Sung Dae
SD
Yoon
Kyungsil
K
Safe
Stephen
S
D000840:Anisoles / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003627:Data Interpretation, Statistical; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D007364:Intercalating Agents / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic
C545255:1,1-bis(3'-indolyl)-1-(p-anisyl)methane; D000840:Anisoles; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; D007364:Intercalating Agents; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C007293:DAPI