Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion.
Programmed cell death 4 (Pdcd4) suppresses neoplastic transformation by inhibiting the activation of c-Jun and consequently AP-1-dependent transcription. We report that Pdcd4 blocks c-Jun activation by inhibiting the expression of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1)/hematopoietic progenitor kinase 1, a kinase upstream of Jun N-terminal kinase (JNK). cDNA microarray analysis of Pdcd4-overexpressing RKO human colon carcinoma cells revealed MAP4K1 as the sole target of Pdcd4 on the JNK activation pathway. Cotransfection of a MAP4K1 promoter-reporter with Pdcd4 demonstrated inhibition of transcription from the MAP4K1 promoter. Ectopic expression of Pdcd4 in metastatic RKO cells suppressed invasion. MAP4K1 activity is functionally significant in invasion, as overexpression of a dominant negative MAP4K1 (dnMAP4K1) mutant in RKO cells inhibited not only c-Jun activation but also invasion. Overexpression of a MAP4K1 cDNA in Pdcd4-transfected cells rescued the kinase activity of JNK. Thus, Pdcd4 suppresses tumor progression in human colon carcinoma cells by the novel mechanism of down-regulating MAP4K1 transcription, with consequent inhibition of c-Jun activation and AP-1-dependent transcription.
Yang
Hsin-Sheng
HS
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. hyang3@uky.edu
Matthews
Connie P
CP
Clair
Timothy
T
Wang
Qing
Q
Baker
Alyson R
AR
Li
Chou-Chi H
CC
Tan
Tse-Hua
TH
Colburn
Nancy H
NH
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D003001:Cloning, Molecular; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D015536:Down-Regulation; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000201:enzymology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D018808:Transcription Factor AP-1; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases