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Under different types of stress such as nutrient deprivation, hypoxia, or chemical poisoning, cells form structures known as “stress granules” (SGs). SGs are dense aggregations in the cytoplasm and are composed of RNA and RNA-binding proteins including GTPase-activating protein (SH3 domain)-binding proteins 1 and 2 (G3BP1 and G3BP2), among others; they protect RNAs from harmful conditions. SGs also act as a decision point for untranslated mRNAs to proceed to further storage, translation reprogramming, or degradation.
As a close relative of G3BP1, G3BP2 has similar domain structures comprising the NTF2-like domain and two RNA-binding motifs. Like G3BP1, G3BP2 is ubiquitously expressed and also contributes to the formation of SGs. However, a subtle distinction between these two G3BP isoforms is found in the number of proline-rich (PxxP) motifs in the central region of the proteins. PxxP motifs represent the minimal SH3 domain-binding consensus sequences. Because SH3 domain-containing proteins are pivotal signal transducers, the variability in PxxP regions suggests that G3BP1 and G3BP2 may associate with different partners to produce distinct cellular outcomes.
G3BP2 and breast tumor
Breast tumors contain tumorigenic cancer cells, termed “tumor-initiating cells” (TICs), which can both replenishing themselves and giving rise to populations of non-tumorigenic breast cancer cells (non-TICs). G3BP2 can regulate breast tumor initiation through the stabilization of Squamous cell carcinoma antigen recognized by T cells 3 (SART3) mRNA, which results in increased expression of the pluripotency transcription factors Octamer-binding protein 4 (Oct-4) and Nanog Homeobox (Nanog). The study shows that G3BP2 is involved in breast tumor initiation and an archetypal small molecule compound, C108, which mitigates this function of G3BP2. Combining structurally related derivatives of compound C108 with standardized treatment can be beneficial for patients with relapsed, drug-resistant, and/or metastatic breast cancer and might improve the overall survival of these patients. Moreover, the potential interplay between SG formation and a breast tumor-initiation program may unveil new targets for anticancer therapy. By coupling a fuller understanding of the molecular underpinnings of the breast TIC phenotype to a repertoire of compounds that can target these effectors, it is likely that targeting stemness may soon become a viable therapeutic strategy in the treatment of breast cancer.
G3BP2 and Prostate cancer
Prostate cancer growth is promoted by the gene regulatory action of androgen receptor (AR) and its downstream signals. The aberrant dysfunction of tumor suppressor p53 has a crucial role in the prognosis of cancer. G3BP2 can regulate androgen-mediate p53 nuclear export by sumoylation with SUMO E3 ligase RAN-binding protein 2 (RanBP2). Moreover, elevated G3BP2 expression repressed docetaxel-mediated apoptosis to promote CRPC tumor growth. It was also revealed that G3BP2 is a prognostic marker in CRPC development of prostate cancer patients.
In the previous analysis, researchers noted that tripartite motif-containing protein 25 (TRIM25) would be a promising candidate of new G3BP2-interacting partners in prostate cancer cells. In the recent study, they provide the first mechanism that TRIM25 modulates the cellular localization of p53 and regulates cell cycle progression as well as anti-apoptotic function. TRIM25 functions through interaction with G3BP2 to negatively regulate p53 activity (Figure 1). They observed that TRIM25 knockdown promoted apoptosis and abolished androgen-mediated p53 nuclear export by the mechanism associated with G3BP2. In addition, TRIM25 overexpression inhibits apoptosis by repressing p53 downstream signals. It demonstrated that high expression of TRIM25 is a novel prognostic factor of prostate cancer patients. Taken together, these findings provide a new oncogenic role of TRIM25 as a p53 modulator by regulating the subcellular localization.
Figure 1. Schematic model of TRIM25 via interaction with G3BP2 for regulating p53 localization.