Abstract 1855: Structural requirements for the association of the ETS domain transcription factor Elk1 and the androgen receptor in enabling the growth of prostate cancer cells

Abstract

Abstract The ETS domain transcription factor Elk1 tethers the androgen receptor (AR) to chromatin, enabling sustained activation of a set of genes critical for cell growth in established prostate cancer cell lines. This role of Elk1 is independent of the ability of Elk1 to transiently activate immediate early genes in response to phosphorylation by ERK. We compared the structural requirements for the association of AR and Elk1 with that for activation of Elk1 by phosphorylation using mammalian one- and two-hybrid assays. The critical polypeptide segments were mapped by systematic deletion mutagenesis. The amino-terminal A/B domain of AR, which lacks the ligand-binding domain (LBD), was adequate for association with Elk1 and to activate Elk1-AR target genes in LNCaP prostate cancer cells. The AR A/B domain also supported hormone-independent growth of LNCaP cells reflecting the ability of overexpressed natural splice variants of AR, which also lack LBD, to support prostate tumor growth. The association of AR with Elk1 did not require ERK1/2 or serum response factor (SRF), which are the known binding partners of Elk1. We identified two sites on Elk1 that are critical for its association with the AR A/B domain as well as the whole AR molecule. One of those sites spans amino acid residues 297 to 317, overlapping one of two ERK docking sites. The other site on Elk1 mapped to amino acid residues 387 to 397, adjacent to the downstream ERK docking site. The results suggest that the association of AR with Elk1 in situ is direct rather than through the Elk1 ternary complex and that the association may be disrupted by small molecules to selectively inhibit growth signaling in prostate cancer cells. Citation Format: Rayna Rosati, Venkatesh Chari, Mugdha Patki, Manohar Ratnam. Structural requirements for the association of the ETS domain transcription factor Elk1 and the androgen receptor in enabling the growth of prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1855. doi:10.1158/1538-7445.AM2015-1855