Similar Datasets
Project description:Prostate cancer (PC) is the most common tumour diagnosis and a serious threat to the lives of men worldwide. It is well recognized that androgens play a unique role in prostate cancer and thus endocrine therapy, represented by androgen deprivation therapy (ADT), is a cornerstone of prostate cancer treatment. However, after ADT treatment, it is inevitable that a number of changes will occur leading from hormone sensitive prostate cancer to castration-resistant prostate cancer (CRPC). RB1 deletion, which is only present in 21% of the population, is the only genomic factor associated with the prognosis of androgen receptor signaling inhibitor therapy. We previously reported that phosphorylated RB has the ability to inhibit p65 in prostate cancer, thereby promoting immune tumour escape and increasing sensitivity to radiotherapy. The N-terminal end of RB also enhances the sensitivity of CDK4/6 inhibitors by recognizing the FXXXV amino acid motif on HDAC5 to down-regulate cell cycle-related genes. Recently, it has been shown that TRIM28 binds to and mediates the ubiquitinated degradation of RB protein. However, the relationship between TRIM24 and RB remains a mystery. In this study, we found that the phosphorylated RB N-terminal can interact with TRIM24 to form a complex that enhances AR signaling. And RB/TRIM24 used DUSP2 as an intermediate bridge to activate the mTOR pathway and promote prostate cancer progression. Finally, we also designed RB-linker-protac, which can attenuate TRIM24 protein levels and inactivate the mTOR signaling pathway, thereby inhibiting prostate cancer. This provides new insights into the treatment of prostate cancer.
2024-05-22 | GSE238209 | GEO
Project description:Prostate cancer (PC) is the most common tumour diagnosis and a serious threat to the lives of men worldwide. It is well recognized that androgens play a unique role in prostate cancer and thus endocrine therapy, represented by androgen deprivation therapy (ADT), is a cornerstone of prostate cancer treatment. However, after ADT treatment, it is inevitable that a number of changes will occur leading from hormone sensitive prostate cancer to castration-resistant prostate cancer (CRPC). RB1 deletion, which is only present in 21% of the population, is the only genomic factor associated with the prognosis of androgen receptor signaling inhibitor therapy. We previously reported that phosphorylated RB has the ability to inhibit p65 in prostate cancer, thereby promoting immune tumour escape and increasing sensitivity to radiotherapy. The N-terminal end of RB also enhances the sensitivity of CDK4/6 inhibitors by recognizing the FXXXV amino acid motif on HDAC5 to down-regulate cell cycle-related genes. Recently, it has been shown that TRIM28 binds to and mediates the ubiquitinated degradation of RB protein. However, the relationship between TRIM24 and RB remains a mystery. In this study, we found that the phosphorylated RB N-terminal can interact with TRIM24 to form a complex that enhances AR signaling. And RB/TRIM24 used DUSP2 as an intermediate bridge to activate the mTOR pathway and promote prostate cancer progression. Finally, we also designed RB-linker-protac, which can attenuate TRIM24 protein levels and inactivate the mTOR signaling pathway, thereby inhibiting prostate cancer. This provides new insights into the treatment of prostate cancer.
2024-05-21 | GSE237930 | GEO
Project description:The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer
| PRJNA998370 | ENA
Project description:The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer [RNA-Seq]
| PRJNA997255 | ENA
Project description:The S249/T252 site of RB enhanced the function of TRIM24 to activate the mTOR signaling pathway through DUSP2 in prostate cancer [ChIP-Seq]
| PRJNA998377 | ENA
Project description:The mammalian immune system has the ability to discriminate between pathogenic microbes and nonpathogenic microbes to control inflammation. Here we investigated the ubiquitination profiles of host proteins after infection of macrophages with a virulent strain of the intracellular bacterium Legionella pneumophila or a nonpathogenic mutant of L. pneumophila. Only infection with pathogenic L. pneumophila resulted in ubiquitination of positive regulators of the metabolic checkpoint kinase mTOR and led to diminished mTOR activity. Detection of pathogen signatures resulted in translational biasing toward proinflammatory cytokines through mTOR-mediated regulation of cap-dependent translation. Thus, there is a pathogen-detection program in macrophages that stimulates protein ubiquitination and the degradation of regulators of mTOR, which suppresses mTOR function and directs a proinflammatory cytokine program.
| S-EPMC3839319 | biostudies-literature
Project description:Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients.
| S-EPMC5124371 | biostudies-literature
Project description:Like tumor cells, DNA viruses have had to evolve mechanisms that uncouple cellular replication from the many intra- and extracellular factors that normally control it. Here we show that adenovirus encodes two proteins that activate the mammalian target of rapamycin (mTOR) for viral replication, even under nutrient/growth factor-limiting conditions. E4-ORF1 mimics growth factor signaling by activating PI3-kinase, resulting in increased Rheb.GTP loading and mTOR activation. E4-ORF4 is redundant with glucose in stimulating mTOR, does not affect Rheb.GTP levels and is the major mechanism whereby adenovirus activates mTOR in quiescent primary cells. We demonstrate that mTOR is activated through a mechanism that is dependent on the E4-ORF4 protein phosphatase 2A-binding domain. We also show that mTOR activation is required for efficient S-phase entry, independently of E2F activation, in adenovirus-infected quiescent primary cells. These data reveal that adenovirus has evolved proteins that activate the mTOR pathway, irrespective of the cellular microenvironment, and which play a requisite role in viral replication.
| S-EPMC556401 | biostudies-literature
Project description:BackgroundThe RB-E2F pathway is conserved in most eukaryotic lineages, including animals and plants. E2F and RB family proteins perform crucial functions in cycle controlling, differentiation, development and apoptosis. However, there are two kinds of E2Fs (repressive E2Fs and active E2Fs) and three RB family members in human. Till now, the detail evolutionary history of these protein families and how RB-E2F pathway evolved in different organisms remain poorly explored.ResultsWe performed a comprehensive evolutionary analysis of E2F, RB and DP (dimerization partners of E2Fs) protein family in representative eukaryotic organisms. Several interesting facts were revealed. First, orthologues of RB, E2F, and DP family are present in several representative unicellular organisms and all multicellular organisms we checked. Second, ancestral E2F, RB genes duplicated before placozoans and bilaterians diverged, thus E2F family was divided into E2F4/5 subgroup (including repressive E2Fs: E2F4 and E2F5) and E2F1/2/3 subgroup (including active E2Fs: E2F1, E2F2 and E2F3), RB family was divided into RB1 subgroup (including RB1) and RBL subgroup (including RBL1 and RBL2). Third, E2F4 and E2F5 share more sequence similarity with the predicted E2F ancestral sequence than E2F1, E2F2 and E2F3; E2F4 and E2F5 also possess lower evolutionary rates and higher purification selection pressures than E2F1, E2F2 and E2F3. Fourth, for RB family, the RBL subgroup proteins possess lower evolutionary rates and higher purification selection pressures compared with RB subgroup proteins in vertebrates,ConclusionsProtein evolutionary rates and purification selection pressures are usually linked with protein functions. We speculated that function conducted by E2F4/5 subgroup and RBL subgroup proteins might mainly represent the ancient function of RB-E2F pathway, and the E2F1/2/3 subgroup proteins and RB1 protein might contribute more to functional diversification in RB-E2F pathway. Our results will enhance the current understanding of RB-E2F pathway and will also be useful to further functional studies in human and other model organisms.
| S-EPMC3224931 | biostudies-literature
Project description:Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) has been reported as an oncogenic gene, affecting various malignant tumors, including endometrial carcinoma, osteosarcoma, and gastric cancer. These effects are mostly due to the enhanced deposition of collagen precursors. However, more studies need to be conducted on how its lysyl hydroxylase function affects cancers like colorectal carcinoma (CRC). Our present results showed that PLOD2 expression was elevated in CRC, and its higher expression was associated with poorer survival. Overexpression of PLOD2 also facilitated CRC proliferation, invasion, and metastasis in vitro and in vivo. In addition, PLOD2 interacted with USP15 by stabilizing it in the cytoplasm and then activated the phosphorylation of AKT/mTOR, thereby promoting CRC progression. Meanwhile, minoxidil was demonstrated to downregulate the expression of PLOD2 and suppress USP15, and the phosphorylation of AKT/mTOR. Our study reveals that PLOD2 plays an oncogenic role in colorectal carcinoma, upregulating USP15 and subsequently activating the AKT/mTOR pathway.
| S-EPMC10394153 | biostudies-literature