L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

Abstract

The transcription factor p53 regulates the expression of genes crucial for biological processes such as cell proliferation, metabolism, cell repair, senescence and apoptosis. Activation of p53 also suppresses neoplastic transformations, thereby inhibiting the growth of mutated and/or damaged cells. p53-binding proteins, such as mouse double minute 2 homolog (MDM2), inhibit p53 activation and thus regulate p53-mediated stress responses. Here, we found that long glucocorticoid-induced leucine zipper (L-GILZ), a recently identified isoform of GILZ, activates p53 and that the overexpression of L-GILZ in p53 þ / þ HCT116 human colorectal carcinoma cells suppresses the growth of xenografts in mice. In the presence of both p53 and MDM2, L-GILZ binds preferentially to MDM2 and interferes with p53/MDM2 complex formation, making p53 available for downstream gene activation. Consistent with this finding, L-GILZ induced p21 and p53 upregulated modulator of apoptosis (PUMA) expression only in p53 þ / þ cells, while L-GILZ silencing reversed the anti-proliferative activity of dexamethasone as well as expression of p53, p21 and PUMA. Furthermore, L-GILZ stabilizes p53 proteins by decreasing p53 ubiquitination and increasing MDM2 ubiquitination. These findings reveal L-GILZ as a regulator of p53 and a candidate for new therapeutic anti-cancer strategies for tumors associated with p53 deregulation.

Yeast two-hybrid screening identified WDR77 as a novel interacting partner of TSC22D2

“…It has been reported that TSC22D1 and TSC22D3 are significantly down-regulated in a wide variety of human tumors and act as tumor suppressor genes [5,[13][14][15][16][17][18][19][20]. Both of these genes inhibit cell proliferation and promote cellular apoptosis through the Ras/Raf signaling pathway and ubiquitin mediated-degradation of p53 [17][18][19][20]. T S C 2 2 D 3 a l s o e x a c t s a n t i -i n f l a m m a t o r y a n d Fig.…”

“…Members of this family have diverse physiological functions, spreading from cell growth [5,6], development [7][8][9], and homeostasis [4] to immune regulation [10][11][12]. TSC22D1 and TSC22D3 are potential tumor suppressors and significantly down-regulated in a wide variety of human tumors [5,[13][14][15][16][17][18][19][20]. TSC22D2 may also anticipate the regulation of cell growth [8].…”

GILZ regulates Th17 responses and restrains IL-17-mediated skin inflammation

“…GILZ was recently independently identified as a key regulator of the Th17 program via binding to the promoters of Il21 and Irf4 and preventing binding of the positive regulators Stat3, RORgt, and Batf [15]. In addition to regulation of effector gene expression, GILZ regulates expression of genes involved in apoptosis (Bcl-X L [43]) and cell cycle entry (p21 and p53 [44]) and may exert an antiproliferative effect via modulation of these pathways in CD4 T cells.…”

Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus

“…GILZ is a transcriptional regulator that binds DNA either as a homodimer, or as part of a heterodimeric complex with other transcriptional regulators including NF-κB and activator protein 1 (AP-1) 11–13. GILZ directly represses gene expression and has been reported to regulate expression of genes involved in apoptosis,14 cell cycle15 and inflammation 9 16–19. GILZ exerts a predominantly anti-inflammatory influence on T cells,18 20–22 macrophages23 and endothelial cells24 and we previously reported that in vivo silencing of GILZ exacerbates, while overexpression abrogates, autoimmune arthritis 9 25.…”