A Feedback Loop between the Androgen Receptor and a NEDD4-binding Protein, PMEPA1, in Prostate Cancer Cells

Abstract

PMEPA1 was identified originally as a highly androgen-inducible gene with prostate-abundant expression that was restricted to prostatic epithelial cells. PMEPA1 protein is a NEDD4 (ubiquitin-protein isopeptide ligase)-binding protein, which negatively regulates prostate cancer cell growth. In this study we establish that PMEPA1 is a direct transcriptional target of the androgen receptor (AR). We also demonstrate that PMEPA1 negatively regulates AR protein levels in different cell culture models. Transient expression of PMEPA1 down-regulates AR protein levels and AR transcriptional targets in prostate cancer cells. Conversely, knockdown of PMEPA1 leads to elevated levels of AR protein, AR transcriptional targets (prostatespecific antigen), and increased cell cycle S phase. We define that the PMEPA1-dependent down-regulation of AR is because of AR ubiquitination and proteasome-mediated degradation. The mutant PMEPA1 (PY1/2 motif mutation) that is impaired in NEDD4 recruitment shows attenuated AR ubiquitination and AR protein down-regulation. These data support the hypothesis that PMEPA1 negatively regulates the stability of AR protein by enhancing AR ubiquitination and proteasome-mediated degradation through NEDD4. The effect of PMEPA1 on AR ubiquitination and degradation appears to be MDM2-independent. Thus, the PMEPA1-AR degradation pathway may represent a new androgen-dependent mechanism for regulating AR levels in prostate epithelial cells. These findings underscore that the decreased PMEPA1 expression frequently noted in prostate cancers may lead to increased AR functions and strengthen the biological role of PMEPA1 in prostate cancers.

The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

“…TMEPAI has been reported to be involved in the degradation of several important proteins, such as TGF-β type I receptor (TβRI) (11) and androgen receptor (AR) (22). However, the specific mechanisms are different.…”

“…However, the specific mechanisms are different. TEMPAI mediates TβRI degradation in lysosomes (11) but mediates AR degradation in proteasomes (22). TMEPAI induces the sequestration of TβRI in lysosomes which is possibly associated with TMEPAI subcellular location because TMEPAI was found to be localized to the lysosomal membrane and increases lysosomal stability (11,23).…”

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

“…In the network of signaling transduction, the positive feedback loop regulation plays important roles in determining the progressive nature of malignant cancer cells including cell proliferation [2][3][4][5] . Extracellular signal-regulated kinase 1/2 (ERK1/2), a major cellular proliferation signaling pathway, is involved in many positive feedback loops.…”

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

“…Because TMEPAI is a direct target gene for TGF-␤ signaling, TMEPAI seems to act as a molecule involved in the negative feedback loop of TGF-␤ signaling (8). Except for its contribution in TGF-␤ signaling, TMEPAI is known to be implicated in the degradation of androgen receptor by the recruiting of the E3 ubiquitin ligase to androgen receptor (9) as well as by cell growth inhibition and p53-induced apoptosis in a context-dependent fashion (10,11). In addition to TGF-␤ stimulation, TMEPAI has been reported to be induced by treatment with androgen, introduction of mutant p53, or activation of the ERK pathway (11)(12)(13).…”