ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells

Abstract

Transforming growth factor-b (TGF-b) 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-b for which the molecular mechanisms are not well understood. In this study, we found that the candidate prostate cancer susceptibility gene ELAC2 potentiates TGF-b/Smadinduced 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-b-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-b is potentiated by ELAC2. Taken together our data indicate an important transcriptional scaffold function for ELAC2 in TGF-b/ Smad signaling mediated growth arrest.

RNAi knockdown of dRNaseZ, the Drosophila homolog of ELAC2, impairs growth of mitotic and endoreplicating tissues

“…In another study, human ELAC2/RNase Z L was shown to participate in the TGF-b/Smad-signaling pathway acting as a scaffold protein recruiting transcription factors and regulating growth arrest of prostate cells (Noda et al, 2006).…”

“…Apparently, the efficiencies of both the sgRNA/RNase Z L and the canonical RISC-based pathways of gene silencing are quite comparable. Another mechanism of gene regulatory function was proposed for RNase Z L in the TGF-b/Smad-signaling pathway that inhibits growth of prostate cells (Noda et al, 2006). Even though RNase Z L itself does not possess transcriptional or DNA binding activities, it can act as a scaffold protein recruiting transcription factors to the TGF-b induced promoters.…”

Transforming growth factor-β and the hallmarks of cancer

“…Cancer cells, particularly those of the breast, elevate their expression of inactive LIP C/EBPβ variants, which uncouples TGF-β from regulation Myc and p15 expression and correlates with metastatic disease development [112]. Along these lines, ELAC2 recently was identified as a transcriptional co-factor that mediates p21 expression in conjunction with Smad2:FAST-1 complexes in prostate epithelial cells [113]. Importantly, loss of ELAC2 in developing and progressing prostate cancers inactivates their ability to undergo growth arrest in response to TGF-β [114].…”

Requirement of TCF7L2 for TGF-β-dependent Transcriptional Activation of the TMEPAI Gene

“…Plasmid Construction-Constitutively active activin receptor-like kinase 5 (ALK5ca)/V5, FLAG-Smad2, FLAG-Smad3, FLAG-Smad4, (CAGA) 12 -luc, FLAG-Smad2⌬exon3, HA-TCF7L2, HA-TCF7L2⌬ , and HA-␤-catenin were described previously (22)(23)(24)(25)(26). Myc-TCF7L2 was kindly gifted by Dr. Watanabe (27).…”