ACS Pharmacol Transl Sci
November 2024
is commonly mutated in cancer, giving rise to loss of wild-type tumor suppressor function and increases in gain-of-function oncogenic roles. Thus, inhibition of mutant p53 and reactivation of wild-type function represents a potential means to target diverse tumor types. ()-1-(4-Methylpiperazin-1-yl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one (NSC59984), first identified from a high-throughput screen, induces wild-type p53 signaling and antiproliferative effects while inhibiting mutant p53 gain-of-function activities.
View Article and Find Full Text PDFProtein phosphatase 1D (PPM1D, Wip1) is induced by the tumor suppressor p53 during DNA damage response signaling and acts as an oncoprotein in several human cancers. Although PPM1D is a potential therapeutic target, insights into its atomic structure were challenging due to flexible regions unique to this family member. Here, we report the first crystal structure of the PPM1D catalytic domain to 1.
View Article and Find Full Text PDFThe human immunodeficiency virus epidemic continues in sub-Saharan Africa, and particularly affects adolescent girls and women who have limited access to antiretroviral therapy. Here we report that the risk of vaginal simian immunodeficiency virus (SIV) acquisition is reduced by more than 90% using a combination of a vaccine comprising V1-deleted (V2 enhanced) SIV envelope immunogens with topical treatment of the zinc-finger inhibitor SAMT-247. Following 14 weekly intravaginal exposures to the highly pathogenic SIV, 80% of a cohort of 20 macaques vaccinated and treated with SAMT-247 remained uninfected.
View Article and Find Full Text PDFis the most commonly mutated gene in cancer, and gain-of-function mutations have wide-ranging effects. Efforts to reactivate wild-type p53 function and inhibit mutant functions have been complicated by the variety of mutations. Identified from a screen, the NSC59984 compound has been shown to restore activity to mutant p53 in colorectal cancer cells.
View Article and Find Full Text PDFWild-type P53-induced phosphatase 1 (WIP1), also known as or PP2Cδ, is a serine/threonine protein phosphatase induced by P53 after genotoxic stress. WIP1 inhibition has been proposed as a therapeutic strategy for P53 wild-type cancers in which it is overexpressed, but this approach would be ineffective in P53-negative cancers. Furthermore, there are several cancers with mutated P53 where WIP1 acts as a tumor suppressor.
View Article and Find Full Text PDFThe wild-type p53 induced phosphatase 1 (Wip1), a member of the serine/threonine-specific PP2C family, is overexpressed in numerous human cancers. Wip1 dephosphorylates p53 as well as several kinases (such as p38 MAPK, ATM, Chk1, and Chk2) in the DNA damage response pathway that are responsible for maintaining genomic stability and preventing oncogenic transformation. As a result, Wip1 is an attractive target for synthetic inhibitors that could be further developed into therapeutics to treat some cancers.
View Article and Find Full Text PDFActivation of T cells upon engagement of the T cell antigen receptor rapidly leads to a number of phosphorylation and plasma membrane recruitment events. For example, translocation of phospholipase-Cγ1 (PLC-γ1) to the plasma membrane and its association with the transmembrane adapter protein LAT and two other adapter proteins, Gads and SLP-76, are critical events in the early T cell activation process. We have previously characterized the formation of a tetrameric LAT-Gads-SLP-76-PLC-γ1 complex by reconstitution in vitro and have also characterized the thermodynamics of tetramer formation.
View Article and Find Full Text PDFPPM1D/Wip1 is a negative regulator of the tumor suppressor p53 and is overexpressed in several human solid tumors. Recent reports associate gain-of-function mutations of PPM1D in immune cells with worse outcomes for several human cancers. Here we show that mice with genetic knockout of Ppm1d or with conditional knockout of Ppm1d in the hematopoietic system, in myeloid cells, or in neutrophils all display significantly reduced growth of syngeneic melanoma or lung carcinoma tumors.
View Article and Find Full Text PDFBecause of microbicide noncompliance and lack of a durable, highly effective vaccine, a combined approach might improve HIV prophylaxis. We tested whether a vaccine-microbicide combination would enhance protection against SIV infection in rhesus macaques. Four macaque groups included vaccine only, vaccine-microbicide, microbicide only, and controls.
View Article and Find Full Text PDFThis year marks the 40th anniversary of the initial identification of p53 as a transformation-related Ag, which was the result of our effort to identify an antigenically distinct tumor Ag of a chemically induced mouse tumor and develop a cancer vaccine. Many researchers at the time viewed this effort as folly. Since then, its characterization has progressed from being an attractive cancer vaccine candidate to recognition as a key player in regulating critical pathways controlling the cell cycle and oncogenesis.
View Article and Find Full Text PDFDysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression.
View Article and Find Full Text PDFWT P53-Induced Phosphatase 1 (WIP1) is a member of the magnesium-dependent serine/threonine protein phosphatase (PPM) family and is induced by P53 in response to DNA damage. In several human cancers, the WIP1 protein is overexpressed, which is generally associated with a worse prognosis. Although WIP1 is an attractive therapeutic target, no potent, selective, and bioactive small-molecule modulator with favorable pharmacokinetics has been reported.
View Article and Find Full Text PDFThe T cell antigen receptor encounters foreign antigen during the immune response. Receptor engagement leads to activation of specific protein tyrosine kinases, which then phosphorylate multiple enzymes and adapter proteins. One such enzyme, phospholipase-Cγ1, is responsible for cleavage of a plasma membrane lipid substrate, a phosphoinositide, into two second messengers, diacylglycerol, which activates several enzymes including protein kinase C, and an inositol phosphate, which induces intracellular calcium elevation.
View Article and Find Full Text PDFMetal-dependent protein phosphatases (PPM) are evolutionarily unrelated to other serine/threonine protein phosphatases and are characterized by their requirement for supplementation with millimolar concentrations of Mg or Mn ions for activity The crystal structure of human PPM1A (also known as PP2Cα), the first PPM structure determined, displays two tightly bound Mn ions in the active site and a small subdomain, termed the Flap, located adjacent to the active site. Some recent crystal structures of bacterial or plant PPM phosphatases have disclosed two tightly bound metal ions and an additional third metal ion in the active site. Here, the crystal structure of the catalytic domain of human PPM1A, PPM1A, complexed with a cyclic phosphopeptide, c(MpSIpYVA), a cyclized variant of the activation loop of p38 MAPK (a physiological substrate of PPM1A), revealed three metal ions in the active site.
View Article and Find Full Text PDFThe wild-type p53 induced phosphatase 1, Wip1 (PP2Cδ), is a protein phosphatase 2C (PP2C) family serine/threonine phosphatase that negatively regulates the function of the tumor suppressor p53 and several of its positive regulators such as ATM, Chk1, Chk2, Mdm2, and p38 MAPK. Wip1 dephosphorylates and inactivates its protein targets, which are critical for cellular stress responses. Additionally, Wip1 is frequently amplified and overexpressed in several human cancer types.
View Article and Find Full Text PDFTP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOFs) distinct from the tumor suppressor activity of the wild-type protein. Tumor-associated macrophages (TAMs), a hallmark of solid tumors, are typically correlated with poor prognosis.
View Article and Find Full Text PDFZAP-70 is a tyrosine kinase that is essential for initiation of T cell antigen receptor (TCR) signaling. We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. Mutant T cells expressing ZAP-70 with an alanine substitution at this residue (ZAP-70) had enhanced TCR proximal signaling and increased effector responses.
View Article and Find Full Text PDFNuclear factor of activated T cells (NFAT) transcription factors are required for induction of T-cell cytokine production and effector function. Although it is known that activation via the T-cell antigen receptor (TCR) results in 2 critical steps, calcineurin-mediated NFAT1 dephosphorylation and NFAT2 up-regulation, the molecular mechanisms underlying each are poorly understood. Here we find that T cell p38, which is activated by an alternative pathway independent of the mitogen-activated protein (MAP) kinase cascade and with different substrate specificities, directly controls these events.
View Article and Find Full Text PDFThe strategy of simultaneously attacking multiple targets is worthy of exploration in the field of microbicide development to combat HIV-1 sequence diversity and minimize the transmission of resistant variants. A combination of S-acyl-2-mercaptobenzamide thioester-10 (SAMT10), an inhibitor of the HIV-1 nucleocapsid protein (NCp7), and the fusion inhibitor sifuvirtide (SFT) may exert synergistic effects, since SFT can block viral fusion at an early stage of the viral cycle and SAMT10 can disrupt viral particles at a later stage. In this study, we investigated the effect of the combination of SAMT10 and SFT on HIV-1 infection using in vitro cell culture and ex vivo mucosal explant models.
View Article and Find Full Text PDFPPM serine/threonine protein phosphatases function in signaling pathways and require millimolar concentrations of Mn or Mg ions for activity. Whereas the crystal structure of human PP2Cα displayed two tightly bound Mn ions in the active site, recent investigations of PPM phosphatases have characterized the binding of a third, catalytically essential metal ion. The binding of the third Mg to PP2Cα was reported to have millimolar affinity and to be entropically driven, suggesting it may be structurally and catalytically important.
View Article and Find Full Text PDFCancer stem cells (CSC) typically over-express aldehyde dehydrogenase (ALDH). Thus, ALDHbright tumor cells represent targets for developing novel cancer prevention/treatment interventions. Loss of p53 function is a common genetic event during cancer development wherein small molecular weight compounds (SMWC) that restore p53 function and reverse tumor growth have been identified.
View Article and Find Full Text PDFProtein interactions are fundamental to the proper functioning of cells, and aberrant formation or regulation of protein interactions is at the heart of many diseases, including cancer. The advancement of methods to study the identity, function, and regulation of protein complexes makes possible the understanding of how those complexes malfunction in human diseases. New methodologies in mass spectrometry, microscopy, and protein structural analysis are rapidly advancing the amount and quality of the data, as well as the level of detail that can be obtained from experiments.
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