Astrocyte elevated gene-1 ( AEG-1 ) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc

Abstract

It is well established that Ha-ras and c-myc genes collaborate in promoting transformation, tumor progression, and metastasis. However, the precise mechanism underlying this cooperation remains unclear. In the present study, we document that astrocyte elevated gene-1 (AEG-1) is a downstream target molecule of Ha-ras and c-myc, mediating their tumor-promoting effects. AEG-1 expression is elevated in diverse neoplastic states, it cooperates with Ha-ras to promote transformation, and its overexpression augments invasion of transformed cells, demonstrating its functional involvement in Ha-ras-mediated tumorigenesis. We now document that AEG-1 expression is markedly induced by oncogenic Ha-ras, activating the phosphatidylinositol 3-kinase signaling pathway that augments binding of c-Myc to key E-box elements in the AEG-1 promoter, thereby regulating AEG-1 transcription. In addition, Ha-ras-mediated colony formation is inhibited by AEG-1 siRNA. This is a demonstration that Ha-ras activation of a tumorpromoting gene is regulated directly by c-Myc DNA binding via phosphatidylinositol 3-kinase signaling, thus revealing a previously uncharacterized mechanism of Ha-ras-mediated oncogenesis through AEG-1.tumor-promoting gene ͉ signaling pathway ͉ transcription T he ras protooncogene is a small GTP͞GDP-binding protein that plays a critical role in cell growth control as a central component of mitogenic signaling (1). Ras activation initiates a complex array of signal transduction pathways including the Raf͞MAPK (ERK) pathway, primarily involved in plasmamembrane-to-nucleus signaling crucial for mitogen-induced cell proliferation (2, 3); the phosphatidylinositol 3-kinase (PI3K)͞ AKT pathway, which is involved in cell survival signaling (4); the Rac͞Rho pathway, involved in cytoskeletal remodeling (5); and Rac͞JNK and Rac͞p38 pathways, both of which appear to be involved in cell stress responses, growth inhibition, and apoptotic signaling (6-8). Activation of Ras signaling pathways is essential for cells to exit a quiescent state and pass through the G 1 phase of the cell cycle (9). Under normal conditions, the action of Ras and other members of the Ras pathway are stringently regulated during the cell cycle and under different growth conditions (10). In a tumor cell, the oncogenic activation of ras is a consequence of point mutations that either impair GTPase activity or enhance GTP-binding affinity, resulting in a highly active proliferative signal (1). In addition, it is possible that the downstream protein targets of that signal transduction pathway might be expressed abnormally. Ras mutations are found in a wide variety of human cancers (11). Therefore, aberrant Ras signaling represents a nodal pathway regulating tumor-cell growth and providing a potential target for cancer therapy (12, 13).We recently reported the cloning and functional characterization of an HIV-1-inducible gene, astrocyte elevated gene-1 (AEG-1), which is induced in primary human fetal astrocytes infected with HIV-1 or treated with gp120 or TNF-␣ (14-1...

AEG‐1 induces gastric cancer metastasis by upregulation of eIF4E expression

“…In recent years, AEG‐1 expression was found to be elevated and correlated with clinical tumour type, stage, metastasis and prognosis in a variety of cancers, including breast 9, lung 10, colorectal 11, cervical 12, 13, head and neck 14, hepatocellular 15 and gastric cancers 16, 17. AEG‐1 has been shown to be transcriptionally up‐regulated by Ha‐Ras‐activated PI3K and c‐Myc 18. Moreover, AEG‐1 activates the PI3K/Akt, MAPK/ERK, NF‐κB and Wnt signalling pathways to promote cell proliferation, survival, metabolism, EMT, migration, invasion, protective autophagy and angiogenesis 19, 20.…”

LYRIC/AEG-1 overexpression modulates BCCIPα protein levels in prostate tumor cells

“…Elevated expression has been reported in breast and prostate tumors, melanoma and glioblastoma [1][2][3][4], and evidence suggests that LYRIC/AEG-1 actively contributes to malignant progression. LYRIC/AEG-1 overexpression activates both NF-kappaB and Akt signaling pathways [5,6], and the protein acts synergistically with Ha-Ras to promote anchorage-independent growth [1,7]. In prostate tumor cell lines, LYRIC/AEG-1 knockdown resulted in reduced viability and invasiveness [3].…”

“…In prostate tumor cell lines, LYRIC/AEG-1 knockdown resulted in reduced viability and invasiveness [3]. Overexpression of LYRIC/AEG-1 in nontumorigenic cells is not sufficient to induce transformation [1,7], but studies to date suggest that LYRIC/AEG-1 is an important factor promoting progression or metastasis of a variety of tumors.…”

Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression

“…LYRIC/ AEG-1 is reported to be regulated by HA-RAS and c-myc (Lee et al, 2006), to suppress activators of apoptosis such as FOXO3a (Kikuno et al, 2007), and to activate nuclear factor-kB which regulates the expression of cell adhesion molecules implicated in cancer progression and metastasis . Recently, it has been shown that LYRIC/AEG-1 is overexpressed in breast and prostate tumourigenesis (Li et al, 2008;Hu et al, 2009;Thirkettle et al, 2009).…”

“…This would increase oncogene expression such as c-myc and a decrease in genes involved in apoptosis (Bernardo et al, 2007) (Figure 4d). C-myc has been shown to bind the promoter region of LYRIC/AEG-1 and regulate its expression (Lee et al, 2006). When LYRIC/AEG-1 expression is tightly regulated in benign tissue, PLZF may repress gene expression; however, during tumourigenesis LYRIC/AEG-1 levels increase, potentially resulting in a reduction of PLZF-mediated repression.…”