ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-beta/Smad-induced growth arrest of prostate cells.
Transforming growth factor-beta (TGF-beta) elicits a potent growth inhibitory effect on many normal cells by binding to specific serine/threonine kinase receptors and activating specific Smad proteins, which regulate the expression of cell cycle genes, including the p21 cyclin-dependent kinase (CDK) inhibitor gene. Interestingly, cancer cells are often insensitive to the anti-mitogenic effects of TGF-beta for which the molecular mechanisms are not well understood. In this study, we found that the candidate prostate cancer susceptibility gene ELAC2 potentiates TGF-beta/Smad-induced transcriptional responses. ELAC2 associates with activated Smad2; the C-terminal MH2 domain of Smad2 interacts with the N-terminal region of ELAC2. Small interfering siRNA-mediated knock-down of ELAC2 in prostate cells suppressed TGF-beta-induced growth arrest. Moreover, ELAC2 was shown to specifically associate with the nuclear Smad2 partner, FAST-1 and to potentiate the interaction of activated Smad2 with transcription factor Sp1. Furthermore, activation of the p21 CDK inhibitor promoter by TGF-beta is potentiated by ELAC2. Taken together our data indicate an important transcriptional scaffold function for ELAC2 in TGF-beta/Smad signaling mediated growth arrest.
Noda
D
D
Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Itoh
S
S
Watanabe
Y
Y
Inamitsu
M
M
Dennler
S
S
Itoh
F
F
Koike
S
S
Danielpour
D
D
ten Dijke
P
P
Kato
M
M
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002455:Cell Division / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
D017931:DNA Primers; C421605:ELAC2 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D051785:Smad Proteins; D016212:Transforming Growth Factor beta