Tip110 Regulates the Cross Talk between p53 and Hypoxia-Inducible Factor 1α under Hypoxia and Promotes Survival of Cancer Cells

Abstract

bHypoxia often occurs under various physiological and pathophysiological conditions, including solid tumors; it is linked to malignant transformation, metastatic progression, and treatment failure or resistance. Tip110 protein plays important roles in several known physiological and pathophysiological processes, including cancers. Thus, in the present study we investigated the regulation of Tip110 expression under hypoxia. Hypoxia led to Tip110 protein degradation through the ubiquitin-proteasome system. Under hypoxia, Tip110 stabilized p53, which in return destabilized Tip110. In addition, Tip110 regulated hypoxia-inducible factor 1␣ (HIF-1␣), likely through enhancement of its protein stability. Furthermore, Tip110 upregulated p300, a known coactivator for both p53 and HIF-1␣. Expression of a p53(22/23) mutant deficient in p300 binding accelerated Tip110 degradation under hypoxia. Tip110 knockdown resulted in the inhibition of cell proliferation and cell death in the presence of p53. Finally, significantly less Tip110, p53, and HIF-1␣ was detected in the hypoxic region of bone metastasis tumors in a mouse model of human melanoma cells. Taken together, these results suggest Tip110 is an important mediator in the cross talk between p53 and HIF-1␣ in response to hypoxic stress. Hypoxia is the common characteristic of many solid tumors. The adaptation of cells to hypoxia is mediated by hypoxiainducible factor (HIF), a transcription factor, at the molecular level (1). Under normal oxygen conditions (normoxia), HIF-1␣ is hydroxylated, which promotes its binding to the ubiquitin ligase von Hippel-Lindau protein (pVHL), thereby targeting it for ubiquitin-proteasome system (UPS)-mediated degradation. However, under hypoxic conditions, HIF-1␣ becomes less hydroxylated, leading to its rapid accumulation and subsequent activation of hundreds of genes involved in cell survival, as well as genes involved in apoptosis (2). This opposing function of HIF in determining different cell fates is dependent on the physiopathological context and differential binding to other key partners, such as tumor suppressor protein p53.Similarly to HIF-1␣, p53 stability is also regulated by the hypoxic condition. p53 plays a crucial role in response to DNA damage, aberrant cell control, apoptosis, and senescence (3, 4). p53 function is constitutively regulated in different types of tumors under hypoxia by different mechanisms, such as p53 mutation, expression of inhibitors, or unknown host regulatory elements leading to induction of resistance to p53-mediated apoptosis. In normal cells, p53 protein expression is maintained at a low, often undetectable level due to ubiquitin-mediated proteasome degradation (5). Upon exposure to stress, such as oncogenic activation and certain hypoxic situations, p53 becomes stabilized. Consequently, p53 activates genes involved in cell cycle regulation and genes involved in apoptotic events (4).HIV-1 Tat-interacting protein 110 (Tip110), also known as "squamous cell carcinoma antigen recognized by T cells 3" (SA...

Tip110/SART3 regulates IL-8 expression and predicts the clinical outcomes in melanoma

“…Several reports had shown that human melanoma cells grown in cultures express and secrete numerous cytokines/growth factors either constitutively or upon induction [ 6 ]. In addition, our previous studies have shown a significant reduction of Tip110 together with TP53 expression in melanoma cells exposed to a hypoxic condition [ 3 ]. Therefore, we examined the expression of selected inflammatory cytokines and growth factors that are important during melanoma progression, metastasis, and survival, in the context of limited Tip110 expression [ 6 ].…”

“…The high expression level of Tip110 has been found in a number of malignant tumor cell lines and cancerous tissues [ 2 ]. However, exposure of highly metastatic melanoma cells to hypoxia led to a significant downregulation of Tip110 together with TP53 in both in vitro and in a melanoma cancer bone metastasis mouse model [ 3 ]. Also, Tip110 expression was found to be dysregulated and correlated with a metastatic phenotype in melanoma and lung adenocarcinoma [ 4 , 5 ].…”

Effect of SNX-2112 on proliferation of esophageal cancer cells via regulation of excision repair cross-complementing 1, epidermal growth factor receptor, and p53 expression

“…p53 plays a major role in transcription in humans and is responsible for maintaining normal cell growth, regulating apoptosis, and preventing malignant transformation in cells (Timani et al, 2015). Mutations in the p53 gene could lead to decreased anticancer activity and promote malignant transformation (Bywater et al, 2012).…”

miRNA regulation of Tip110 expression and self-renewal and differentiation of human CD34+ hematopoietic cells

“…cDNAs were used for qPCR performed by Power SYBR® Green PCR kit (Life Technologies, Grand Island, NY, USA) according to the manufacturer's instructions. Primers for Tip110 and actin were described previously [ 18 ]. The qPCR program consisted of 1 cycle of 95°C for 10 min; 40 cycles of 95°C for 15 sec and 60°C for 1 min.…”