Cancer is the second leading cause of human death globally. PI3K/Akt/mTOR signaling is one of the most frequently dysregulated signaling pathways observed in cancer patients that plays crucial roles ...in promoting tumor initiation, progression and therapy responses. This is largely due to that PI3K/Akt/mTOR signaling is indispensable for many cellular biological processes, including cell growth, metastasis, survival, metabolism, and others. As such, small molecule inhibitors targeting major kinase components of the PI3K/Akt/mTOR signaling pathway have drawn extensive attention and been developed and evaluated in preclinical models and clinical trials. Targeting a single kinase component within this signaling usually causes growth arrest rather than apoptosis associated with toxicity-induced adverse effects in patients. Combination therapies including PI3K/Akt/mTOR inhibitors show improved patient response and clinical outcome, albeit developed resistance has been reported. In this review, we focus on revealing the mechanisms leading to the hyperactivation of PI3K/Akt/mTOR signaling in cancer and summarizing efforts for developing PI3K/Akt/mTOR inhibitors as either mono-therapy or combination therapy in different cancer settings. We hope that this review will facilitate further understanding of the regulatory mechanisms governing dysregulation of PI3K/Akt/mTOR oncogenic signaling in cancer and provide insights into possible future directions for targeted therapeutic regimen for cancer treatment, by developing new agents, drug delivery systems, or combination regimen to target the PI3K/Akt/mTOR signaling pathway. This information will also provide effective patient stratification strategy to improve the patient response and clinical outcome for cancer patients with deregulated PI3K/Akt/mTOR signaling.
Sensing invasive cytosolic DNA is an integral component of innate immunity. cGAS was identified in 2013 as the major cytosolic DNA sensor that binds dsDNA to catalyze the synthesis of a special ...asymmetric cyclic-dinucleotide, 2'3'-cGAMP, as the secondary messenger to bind and activate STING for subsequent production of type I interferons and other immune-modulatory genes. Hyperactivation of cGAS signaling contributes to autoimmune diseases but serves as an adjuvant for anticancer immune therapy. On the other hand, inactivation of cGAS signaling causes deficiency to sense and clear the viral and bacterial infection and creates a tumor-prone immune microenvironment to facilitate tumor evasion of immune surveillance. Thus, cGAS activation is tightly controlled. In this review, we summarize up-to-date multilayers of regulatory mechanisms governing cGAS activation, including cGAS pre- and post-translational regulations, cGAS-binding proteins, and additional cGAS regulators such as ions and small molecules. We will also reveal the pathophysiological function of cGAS and its product cGAMP in human diseases. We hope to provide an up-to-date review for recent research advances of cGAS biology and cGAS-targeted therapies for human diseases.
Aberrant activation of AKT disturbs the proliferation, survival and metabolic homeostasis of various human cancers. Thus, it is critical to understand the upstream signalling pathways governing AKT ...activation. Here, we report that AKT undergoes SETDB1-mediated lysine methylation to promote its activation, which is antagonized by the Jumonji-family demethylase KDM4B. Notably, compared with wild-type mice, mice harbouring non-methylated mutant Akt1 not only exhibited reduced body size but were also less prone to carcinogen-induced skin tumours, in part due to reduced AKT activation. Mechanistically, the interaction of phosphatidylinositol (3,4,5)-trisphosphate with AKT facilitates its interaction with SETDB1 for subsequent AKT methylation, which in turn sustains AKT phosphorylation. Pathologically, genetic alterations, including SETDB1 amplification, aberrantly promote AKT methylation to facilitate its activation and oncogenic functions. Thus, AKT methylation is an important step, synergizing with PI3K signalling to control AKT activation. This suggests that targeting SETDB1 signalling could be a potential therapeutic strategy for combatting hyperactive AKT-driven cancers.
Structural basis of nucleosome-dependent cGAS inhibition Boyer, Joshua A; Spangler, Cathy J; Strauss, Joshua D ...
Science (American Association for the Advancement of Science),
10/2020, Letnik:
370, Številka:
6515
Journal Article
Recenzirano
Odprti dostop
Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) recognizes cytosolic foreign or damaged DNA to activate the innate immune response to infection, inflammatory ...diseases, and cancer. By contrast, cGAS reactivity against self-DNA in the nucleus is suppressed by chromatin tethering. We report a 3.3-angstrom-resolution cryo-electron microscopy structure of cGAS in complex with the nucleosome core particle. The structure reveals that cGAS uses two conserved arginines to anchor to the nucleosome acidic patch. The nucleosome-binding interface exclusively occupies the strong double-stranded DNA (dsDNA)-binding surface on cGAS and sterically prevents cGAS from oligomerizing into the functionally active 2:2 cGAS-dsDNA state. These findings provide a structural basis for how cGAS maintains an inhibited state in the nucleus and further exemplify the role of the nucleosome in regulating diverse nuclear protein functions.
The evolutionarily conserved mTOR signaling pathway plays essential roles in cell growth, proliferation, metabolism and responses to cellular stresses. Hyperactivation of the mTOR signaling is ...observed in virtually all solid tumors and has been an attractive drug target. In addition to changes at genetic levels, aberrant activation of the mTOR signaling is also a result from dysregulated posttranslational modifications on key pathway members, such as phosphorylation that has been extensively studied. Emerging evidence also supports a critical role for ubiquitin-mediated modifications in dynamically regulating the mTOR signaling pathway, while a comprehensive review for relevant studies is missing. In this review, we will summarize characterized ubiquitination events on major mTOR signaling components, their modifying E3 ubiquitin ligases, deubiquitinases and corresponding pathophysiological functions. We will also reveal methodologies that have been used to identify E3 ligases or DUBs to facilitate the search for yet-to-be discovered ubiquitin-mediated regulatory mechanisms in mTOR signaling. We hope that our review and perspectives provide rationales and strategies to target ubiquitination for inhibiting mTOR signaling to treat human diseases.
Polyubiquitylation is canonically viewed as a posttranslational modification that governs protein stability or protein-protein interactions, in which distinct polyubiquitin linkages ultimately ...determine the fate of modified protein(s). We explored whether polyubiquitin chains have any nonprotein-related function. Using in vitro pull-down assays with synthetic materials, we found that polyubiquitin chains with the Lys
(K63) linkage bound to DNA through a motif we called the "DNA-interacting patch" (DIP), which is composed of the adjacent residues Thr
, Lys
, and Glu
Upon DNA damage, the binding of K63-linked polyubiquitin chains to DNA enhanced the recruitment of repair factors through their interaction with an Ile
patch in ubiquitin to facilitate DNA repair. Furthermore, experimental or cancer patient-derived mutations within the DIP impaired the DNA binding capacity of ubiquitin and subsequently attenuated K63-linked polyubiquitin chain accumulation at sites of DNA damage, thereby resulting in defective DNA repair and increased cellular sensitivity to DNA-damaging agents. Our results therefore highlight a critical physiological role for K63-linked polyubiquitin chains in binding to DNA to facilitate DNA damage repair.
mTOR serves as a central regulator of cell growth and metabolism by forming two distinct complexes, mTORC1 and mTORC2. Although mechanisms of mTORC1 activation by growth factors and amino acids have ...been extensively studied, the upstream regulatory mechanisms leading to mTORC2 activation remain largely elusive. Here, we report that the pleckstrin homology (PH) domain of SIN1, an essential and unique component of mTORC2, interacts with the mTOR kinase domain to suppress mTOR activity. More importantly, PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation. Mutating critical SIN1 residues that mediate PtdIns(3,4,5)P3 interaction inactivates mTORC2, whereas mTORC2 activity is pathologically increased by patient-derived mutations in the SIN1-PH domain, promoting cell growth and tumor formation. Together, our study unravels a PI3K-dependent mechanism for mTORC2 activation, allowing mTORC2 to activate AKT in a manner that is regulated temporally and spatially by PtdIns(3,4,5)P3.
The SIN1-PH domain interacts with the mTOR kinase domain to suppress mTOR activity, and PtdIns(3,4,5)P3 binds the SIN1-PH domain to release its inhibition on the mTOR kinase domain, leading to mTORC2 activation. Cancer patient-derived SIN1-PH domain mutations gain oncogenicity by loss of suppressing mTOR activity as a means to facilitate tumorigenesis.
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•A total of 643 ARGs subtypes belonging to 22 different ARG types were identified.•The profiles of ARGs shown a city functional region dependent pattern.•Airborne ARGs from the ...hospital exhibited higher ARG abundance and richness, may be the hotspots of resistant genes of multidrug and quinolone.•Environmental ARGs from suburban community could be explained by human fecal pollution, and crAssphage could be applied to predict the abundance of ARGs.
Environmental antibiotic resistance genes (ARGs) have received much attention, while the characteristics of ARGs carried by particulate matter (PM) as a function of urban functional region are almost unknown. In this study, ARGs carried by PM2.5 and PM10 in an urban hospital, a nearby urban community and the nearest suburban community were detected using metagenomics. In total, 643 ARG subtypes belonging to 22 different ARG types were identified. The chloramphenicol exporter gene, sul1, bacA, and lnuA were the most abundant ARG subtypes in all air samples. The hospital exhibited higher ARG abundance and richness than the nearby communities. ARG profiles depended on functional region: hospital and suburban samples clustered separately, and samples from the nearby urban community interspersed among them. The representation of multidrug and quinolone resistance genes decayed with distance from the hospital to the urban community to the suburban community, indicating that hospital PM may be a hotspot for ARGs encoding proteins conferring multidrug and quinolone resistance. Airborne ARGs carried by PM in the hospital environment were more closely associated with clinically important pathogens than were those in nearby communities. In particular, carbapenemase genes, including blaNDM,blaKPC,blaIMP,blaVIM,and blaOXA-48, were discovered in hospital PM. In the suburban community, crAssphage, a human host-specific bacteriophage, was applied to predict ARG abundance and found to be enriched due to anthropogenic pollution but showed no clear evidence for ARG selection. In the hospital and the nearby urban community, the drivers of ARGs were complex. Our results highlighted that PM ARGs were closely related to human activities and revealed a potential hotspot, which could provide new evidence for further research and consequently mitigate the formation of airborne ARGs and transfer risks.
The Hippo and mammalian target of rapamycin complex 1 (mTORC1) pathways are the two predominant growth-control pathways that dictate proper organ development. We therefore explored potential ...crosstalk between these two functionally relevant pathways to coordinate their growth-control functions. We found that the LATS1 and LATS2 kinases, the core components of the Hippo pathway, phosphorylate S606 of Raptor, an essential component of mTORC1, to attenuate mTORC1 activation by impairing the interaction of Raptor with Rheb. The phosphomimetic Raptor-S606D knock-in mutant led to a reduction in cell size and proliferation. Compared with Raptor
mice, Raptor
knock-in mice exhibited smaller livers and hearts, and a significant inhibition of elevation in mTORC1 signalling induced by Nf2 or Lats1 and Lats2 loss. Thus, our study reveals a direct link between the Hippo and mTORC1 pathways to fine-tune organ growth.
The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is ...currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.
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•The E3 ubiquitin ligase SPOP promotes ERG degradation in a CKI-dependent manner•Prostate cancer-associated SPOP mutants fail to promote ERG destruction•ERG fusion proteins evade SPOP-mediated degradation and could be restored by CKI•Etoposide-induced ERG fusion protein degradation depends on SPOP and CKI
Gan et al. report that the Cullin 3SPOP E3 ubiquitin ligase plays a critical tumor-suppressive role in prostate cancer by negatively controlling ERG stability. Therefore, either SPOP mutation or ERG fusion can lead to elevated ERG protein levels by evading the SPOP-mediated degradation pathway to promote prostate cancer progression.
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