Disease relevance of ARHGAP24

• Knockdown of p73 protein, achieved by adenovirus delivery of p73 antisense and by small interfering RNA into ECs, demonstrated the importance of this protein in EC function [1].
• Our analysis of neuroblastoma cell lines with 1p and p73 loss of heterozygosity failed to detect coding sequence mutations in remaining p73 alleles [2].
• By immunohistochemistry, we detected p73 protein in 61 (32%) of the 193 carcinomas examined [3].
• Multivariate Cox survival analysis identified the age of the patient, p73 expression status, co-existing cirrhosis, and Edmondson grade as independent prognostic factors [3].
• To investigate the possibility of genetic alteration of p73 in leukemia and lymphoma, we examined 55 cell lines and 39 patient samples together with 17 nonhematopoietic cancer cell lines [4].

High impact information on ARHGAP24

• Nuclear c-Abl seems to interact with the p53 homolog p73 to elicit apoptosis [5].
• We propose that the disregulation of p73 contributes to tumorigenesis and that p53-related proteins operate in a network of developmental and cell cycle controls [2].
• We describe a gene encoding p73, a protein that shares considerable homology with the tumor suppressor p53. p73 maps to 1p36, a region frequently deleted in neuroblastoma and other tumors and thought to contain multiple tumor suppressor genes [2].
• This gene, called p73, maps to the short arm of chromosome 1, and is found in a region that is frequently deleted in neuroblastomas [6].
• Here we show that p73 can, at least when overproduced, activate the transcription of p53-responsive genes and inhibit cell growth in a p53-like manner by inducing apoptosis (programmed cell death) [6].

Chemical compound and disease context of ARHGAP24

• The p73-p300 interaction was confirmed in vitro by glutathione S-transferase-protein association assays and in vivo by coimmunoprecipitating the overexpressed p300 and p73 in human p53-free small-cell lung carcinoma H1299 or osteosarcoma Saos-2 cells [7].
• To determine whether p73 can sensitize cancer cells to apoptosis by DNA damage agents, several MCF7 adenocarcinoma cell lines that inducibly express p73 or p53 under a tetracycline-regulated promoter were generated [8].
• NH2-terminally truncated p73 isoforms were of significant clinical effect by providing an additional unfavorable factor for response to platinum-based chemotherapy and survival in p53 mutant ovarian cancers [9].
• Here, we compared for the first time to our knowledge p73 and p63 activation in various breast cancer (BC) cell lines after Adriamycin (ADR) treatment, an agent considered as mandatory in breast cancer chemotherapy [10].
• 5-Aza-2'-deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia [11].

Biological context of ARHGAP24

• A mutant R82A alteration achieved a similar phenotype in vitro to the antisense, demonstrating the importance of the GTPase-activating protein activity to p73 function [1].
• Recent evidence indicates that the p53 tumor suppressor protein, and its related family member, p73, play an essential role in regulating neuronal apoptosis in both the developing and injured, mature nervous system [12].
• Inactivation of the GAP domain by a point mutation does not abolish the effect of RC-GAP72 on actin stress fibers but moderates its capability to induce membrane protrusions [13].
• Transient transfection experiments indicated that overexpression of Bcr/Abl in 293T cells is able to activate p38 MAPK or induce p73 stabilization, suggesting that c-Abl and Bcr/Abl share some biological substrates [14].
• DNA damage-triggered signaling and execution of apoptosis is cell-type- and genotoxin-specific depending on the p53 (p63 and p73) status, death-receptor responsiveness, MAP-kinase activation and, most importantly, DNA repair capacity [15].

Anatomical context of ARHGAP24

• Expression profiling of p73 shows that it is vascular cell-selective, being highly expressed in ECs and smooth-muscle cells but not in other cell types [1].
• Overexpression of RC-GAP72 in fibroblasts induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia [13].
• Our data imply that the cytoskeletal localization of RC-GAP72 and its interaction with GTPases are essential for its effect on the integrity of actin stress fibers, whereas the induction of lamellipodia and filopodia depends on the activity of the GAP domain irrespective of binding to the actin cytoskeleton [13].
• Nuclear Factor kappa-B appears to be required to prevent p73-induced apoptosis triggered by primary T cell activation [16].
• Both gamma and delta p73 variants are expressed in human peripheral blood lymphocytes, primary keratinocytes, and different tumor cell lines, including neuroblastoma, glioblastoma, melanoma, hepatoma, and leukemia [17].

Associations of ARHGAP24 with chemical compounds

• Moreover, stimulation of the p73 proapoptotic function by cisplatin requires PMS2 [18].
• The tyrosine kinase, Src, phosphorylates Wwox at tyrosine 33 in the first WW domain and enhances its binding to p73 [19].
• This E2F1-mediated apoptosis is neither p53- nor p73-dependent but proceeds through selective induction of proapoptotic BH3-only protein Bim [20].
• Conversely, CLL cells transduced with an imatinib-resistant c-Abl mutant could be induced by CD154 to express p73 and Bid even when treated with imatinib [21].
• Tat bound to the N-terminal region of p73 spanning amino acids 1 to 120, and this interaction required the cysteine-rich domain (amino acids 30 to 40) of Tat [22].

Regulatory relationships of ARHGAP24

• We propose that RC-GAP72 affects cellular morphology by targeting activated Cdc42 and Rac1 GTPases to specific subcellular sites, triggering local morphological changes [13].

Other interactions of ARHGAP24

• Identification and characterization of ARHGAP24 and ARHGAP25 genes in silico [23].
• A vascular cell-restricted RhoGAP, p73RhoGAP, is a key regulator of angiogenesis [1].

Analytical, diagnostic and therapeutic context of ARHGAP24

• Altogether, our findings identify YAP as a key determinant of p73 gene targeting in response to DNA damage [24].
• A two-hybrid assay was used to characterize the homodimeric and heterodimeric interactions between the p73 variants, and showed that neither p73gamma nor p73delta interact with p53, whereas p73gamma showed strong interactions with all p73 isoforms, and p73delta binds efficiently p73alpha and p73gamma but only weakly p73beta [17].
• RESULTS: RNA transcripts encoding p73 were detected by in situ hybridization in tumor cells but not in stromal, endothelial, or inflammatory cells or in cholangiocytes [3].
• These results indicate that CD154 can sensitize leukemia cells to apoptosis via the c-Abl-dependent activation of p73 and mitigate the resistance of p53-deficient CLL cells to anticancer drug therapy [21].
• Neither homologous deletion nor rearrangement of the p73 gene were found by Southern blot analysis in any of the cell lines that lack expression of p73 [4].

References