XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313

Abstract

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a tumor suppressor that is frequently inactivated in many human cancers. However, the molecular mechanism underlying its growthinhibitory function remains largely unknown. Here, we report that XAF1 forms a positive feedback loop with p53 and acts as a molecular switch in p53-mediated cell-fate decisions favoring apoptosis over cell-cycle arrest. XAF1 binds directly to the N-terminal prolinerich domain of p53 and thus interferes with E3 ubiquitin ligase MDM2 binding and ubiquitination of p53. XAF1 stimulates homeodomaininteracting protein kinase 2 (HIPK2)-mediated Ser-46 phosphorylation of p53 by blocking E3 ubiquitin ligase Siah2 interaction with and ubiquitination of HIPK2. XAF1 also steps up the termination of p53-mediated cell-cycle arrest by activating zinc finger protein 313 (ZNF313), a p21 WAF1 -targeting ubiquitin E3 ligase. XAF1 interacts with p53, Siah2, and ZNF313 through the zinc finger domains 5, 6, and 7, respectively, and truncated XAF1 isoforms preferentially expressed in cancer cells fail to form a feedback loop with p53. Together, this study uncovers a novel role for XAF1 in p53 stress response, adding a new layer of complexity to the mechanisms by which p53 determines cellfate decisions.

Systemic genome screening identifies the outcome associated focal loss of long noncoding RNA PRAL in hepatocellular carcinoma

“…Although most of the sequence of the lncRNA-PRAL overlaps in antisense with the 3 0 untranslated region of XAF1 protein-coding gene, which is known to regulate apoptosis, (24,25) we did not find any significant changes of XIAP-associated factor 1 (XAF1) messenger RNA (mRNA) or protein in lncRNA-PRAL over-or downexpressed SMMC-7721 and HCCLM3 cells (Supporting Fig. 7).…”

Multiple genes identified as targets for 20q13.12–13.33 gain contributing to unfavorable clinical outcomes in patients with hepatocellular carcinoma

“…Of the 19 genes, DDX27, B4GALT5, RNF114, ZFP64, and PFDN4 may be the probable target genes contributing together to the unfavorable outcomes due to correlation with progressive cancer behaviors. RNF114 is an ubiquitin E3 ligase that has a critical role in the regulation of cell cycle progression, differentiation and apoptosis [35][36][37]. In many types of cancer, RNF114 displays a frequent copy number gain and is commonly overexpressed [36,38,39], suggesting its oncogenic property.…”

RASSF1A Directly Antagonizes RhoA Activity through the Assembly of a Smurf1-Mediated Destruction Complex to Suppress Tumorigenesis

“…Immunoprecipitation (IP) assays were carried out as described previously (21). Antibodies specific for RASSF1A (eB114), Smurf1 (sc-25510), phospho-MLCl (Ser19, #3671), RhoA (sc-418), Rac1 (sc-95), CDC42 (sc-6083), RhoGAP (sc-30206), RhoGEF (sc-20804), b-tubulin (T0198), and Actin (sc-1616) were purchased from eBioscience, Santa Cruz Biotechnology, Cell Signaling Technology, and Sigma-Aldrich.…”

“…Mouse tumor xenograft assay was carried out as described previously (21). For tumor cell colonization assay, A549 cells were injected intravenously and numbers of nodules in the lungs were counted after 20 days of injection.…”