Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Cell ; 180(3): 471-489.e22, 2020 02 06.
Article in English | MEDLINE | ID: mdl-32004464

ABSTRACT

Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 µg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.


Subject(s)
Broadly Neutralizing Antibodies/immunology , HIV Antibodies/immunology , HIV Infections/immunology , HIV-1/immunology , env Gene Products, Human Immunodeficiency Virus/immunology , Animals , Antibodies, Monoclonal/immunology , Binding Sites , CD4 Antigens/metabolism , CHO Cells , Cohort Studies , Cricetulus , Epitopes/immunology , Female , HEK293 Cells , HIV Infections/prevention & control , HIV Infections/virology , Heterografts , Humans , Male , Mice , Mice, Inbred NOD , Middle Aged , Mutation , Protein Binding/immunology , env Gene Products, Human Immunodeficiency Virus/genetics
2.
Cell Rep ; 15(4): 843-856, 2016 Apr 26.
Article in English | MEDLINE | ID: mdl-27149849

ABSTRACT

Upon growth factor stimulation or in some EGFR mutant cancer cells, PKM2 translocates into the nucleus to induce glycolysis and cell growth. Here, we report that nuclear PKM2 binds directly to poly-ADP ribose, and this PAR-binding capability is critical for its nuclear localization. Accordingly, PARP inhibition prevents nuclear retention of PKM2 and therefore suppresses cell proliferation and tumor growth. In addition, we found that PAR level correlates with nuclear localization of PKM2 in EGFR mutant brain and lung cancers, suggesting that PAR-dependent nuclear localization of PKM2 likely contributes to tumor progression in EGFR mutant glioblastoma and lung cancers. In addition, some EGFR-inhibitor-resistant lung cancer cells are sensitive to PARP inhibitors. Taken together, our data indicate that suppression of PKM2 nuclear function by PARP inhibitors represents a treatment strategy for EGFR-inhibitor-resistant cancers.

3.
Cell Rep ; 13(3): 524-532, 2015 Oct 20.
Article in English | MEDLINE | ID: mdl-26456820

ABSTRACT

As the key effector in the Hippo pathway, YAP was identified as an oncoprotein whose expression is elevated in various human cancers. However, the development of potentially therapeutic compounds targeting YAP has been slow and limited. Here, we find that tankyrase inhibitors suppress YAP activity. This effect is mediated by anigomotin (AMOT) family proteins. Tankyrases associate with AMOT family proteins and promote their degradation through E3 ligase RNF146. By antagonizing tankyrase activity, tankyrase inhibitors stabilize AMOT family proteins, thereby suppressing YAP oncogenic functions. Together, our studies not only demonstrate the tankyrase-RNF146-AMOT axis as an upstream pathway regulating YAP but also reveal a therapeutic opportunity in targeting YAP for cancer treatment.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Enzyme Inhibitors/pharmacology , Intercellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Phosphoproteins/metabolism , Proteolysis , Tankyrases/antagonists & inhibitors , Angiomotins , HEK293 Cells , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , MCF-7 Cells , Microfilament Proteins , Protein Binding , Protein Stability , Sulfones/pharmacology , Tankyrases/metabolism , Transcription Factors , Triazoles/pharmacology , Ubiquitin-Protein Ligases/metabolism , YAP-Signaling Proteins
4.
Dev Cell ; 32(6): 707-18, 2015 Mar 23.
Article in English | MEDLINE | ID: mdl-25805136

ABSTRACT

Dishevelled (DVL) proteins serve as crucial regulators that transduce canonical Wnt signals to the GSK3ß-destruction complex, resulting in the stabilization of ß-catenin. Emerging evidence underscores the nuclear functions of DVLs, which are critical for Wnt/ß-catenin signaling. However, the mechanism underlying DVL nuclear localization remains poorly understood. Here we discovered two Forkhead box (FOX) transcription factors, FOXK1 and FOXK2, as bona fide DVL-interacting proteins. FOXK1 and FOXK2 positively regulate Wnt/ß-catenin signaling by translocating DVL into the nucleus. Moreover, FOXK1 and FOXK2 protein levels are elevated in human colorectal cancers and correlate with DVL nuclear localization. Conditional expression of Foxk2 in mice induced intestinal hyper-proliferation that featured enhanced DVL nuclear localization and upregulated Wnt/ß-catenin signaling. Together, our results not only reveal a mechanism by which DVL is translocated into the nucleus but also suggest unexpected roles of FOXK1 and FOXK2 in regulating Wnt/ß-catenin signaling.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Forkhead Transcription Factors/metabolism , Phosphoproteins/metabolism , Wnt Proteins/metabolism , beta Catenin/metabolism , Active Transport, Cell Nucleus , Animals , Binding Sites/genetics , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Proliferation , Colorectal Neoplasms/metabolism , Dishevelled Proteins , Female , Forkhead Transcription Factors/biosynthesis , HEK293 Cells , HT29 Cells , HeLa Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Nude , Neoplasm Transplantation , Protein Binding , Transcriptional Activation , Transplantation, Heterologous , Wnt Signaling Pathway
SELECTION OF CITATIONS
SEARCH DETAIL
...