DNA damage response (DDR) acts as a tumorigenesis barrier, and any defects in the DDR machinery may lead to cancer. SOX4 expression is elevated in many types of tumors; however, its role in DDR is still largely unknown. Here, we show that SOX4, a new DNA damage sensor, is required for the activation of p53 tumor suppressor in response to DNA damage. Notably, SOX4 interacts with and stabilizes p53 protein by blocking Mdm2-mediated p53 ubiquitination and degradation. Furthermore, SOX4 enhances p53 acetylation by interacting with p300/CBP and facilitating p300/CBP/p53 complex formation. In concert with these results, SOX4 promotes cell cycle arrest and apoptosis, and it inhibits tumorigenesis in a p53-dependent manner. Therefore, these findings highlight SOX4 as a potential key factor in regulating DDR-associated cancer.Mdm2 ͉ ubiquitination ͉ tumorigenesis D NA damage response (DDR), a highly conserved response to genotoxic stresses, is the guardian of genomic integrity (1, 2). It has been shown that DDR serves as a barrier to constrain tumor progression in its early stages by inducing cell cycle arrest, DNA repair, or apoptosis (3). A number of components are involved in cellular DDR machinery, in which ATM-Chk2-p53 and ATRChk1-p53 cascade are the key signaling pathways involved (2). A central component of DDR, p53, is one of the most important tumor suppressor proteins (4-8). The major consequence of p53 activation upon DNA damage is the induction of specific target genes, such as p21 WAF , Bax, and Puma, to initiate cell cycle arrest, apoptosis, and DNA repair (4). Cells lacking functional p53 exhibit a partial deficiency in DNA damage repair, resulting in uncontrolled cell proliferation and malignancy. Indeed, p53 gene is either lost or mutated in more than half of all human cancers (9). Around p53 there is a highly regulated network consisting of numerous proteins that interact with p53 and regulate its activity by protein stabilization, posttranscriptional modifications, protein-protein interaction, and protein subcellular localization (10), among which stabilization of p53 is presumed to play a major role in its activation. Under normal conditions, amount and activity of p53 are maintained at low levels by Mdm2, a ubiquitin E3 ligase, which binds to the N terminus of p53 and targets its C-terminal lysine residues for ubiquitination and degradation (11,12). However, in response to DNA damage, p53 protein is rapidly stabilized and activated mostly through multiple posttranslational modifications, such as phosphorylation and acetylation of specific residues in the N-terminal and C-terminal domains. DNA damage-induced p53 phosphorylation, which is mediated by ATM kinase (13, 14), contributes to p53 stability (15). Acetylation of p53 C-terminal lysine residues in p53 stabilizes the protein by preventing Mdm2-mediated ubiquitination of the same residues (16,17). In addition, the activity of p53 is also modulated by its recruitment of transcriptional coactivators or corepressors.SOX4 is a member of the SOX (SRY-re...

Despite rapid progress in elucidating the molecular mechanisms of activation of the kinase IKK, the processes that regulate IKK deactivation are still unknown. Here we demonstrate that CUE domain-containing 2 (CUEDC2) interacted with IKKalpha and IKKbeta and repressed activation of the transcription factor NF-kappaB by decreasing phosphorylation and activation of IKK. Notably, CUEDC2 also interacted with GADD34, a regulatory subunit of protein phosphatase 1 (PP1). We found that IKK, CUEDC2 and PP1 existed in a complex and that IKK was released from the complex in response to inflammatory stimuli such as tumor necrosis factor. CUEDC2 deactivated IKK by recruiting PP1 to the complex. Therefore, CUEDC2 acts as an adaptor protein to target IKK for dephosphorylation and inactivation by recruiting PP1.

Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain-containing protein-2 (CUEDC2), a ubiquitin-binding motif-containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.

Accumulated evidence indicates that progesterone receptors (PR) are involved in proliferation of breast cancer cells and are implicated in the development of breast cancer. In this paper, a yeast two-hybrid screen for PR led to the identification of CUE domain containing 2 (CUEDC2), whose function is unknown. Our results demonstrate that CUEDC2 interacts with PR and promotes progesterone-induced PR degradation by the ubiquitinproteasome pathway. The inhibition of endogenous CUEDC2 by siRNA nearly abrogated the progesteroneinduced degradation of PR, suggesting that CUEDC2 is involved in progesterone-induced PR ubiquitination and degradation. Moreover, we identify the sumoylation site Lys-388 of PR as the target of CUEDC2-promoted ubiquitination. CUEDC2 decreases the sumoylation while promoting ubiquitination on Lys-388 of PRB. We also show that CUEDC2 represses PR transactivation, inhibits the ability of PR to stimulate rapid MAPK activity, and impairs the effect of progesterone on breast cancer cell growth. Therefore, our results identify a key post-translational mechanism that controls PR protein levels and for the first time provide an important insight into the function of CUEDC2 in breast cancer proliferation.

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