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Research paper thumbnail of PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer

Science translational medicine, Jan 15, 2015

Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER... more Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase α (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of up-regulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on tran...

Research paper thumbnail of Antagonism of EGFR and HER3 Enhances the Response to Inhibitors of the PI3K-Akt Pathway in Triple-Negative Breast Cancer

Science Signaling, 2014

The following resources related to this article are available online at http://stke.sciencemag.org.

Research paper thumbnail of The CDK inhibitor p21Cip1/WAF1 is induced by FcγR activation and restricts HIV-1 replication in human macrophages

Research paper thumbnail of hnRNP A1 Nucleocytoplasmic Shuttling Activity Is Required for Normal Myelopoiesis and BCR/ABL Leukemogenesis

Molecular and Cellular Biology, 2002

hnRNP A1 is a nucleocytoplasmic shuttling heterogeneous nuclear ribonucleoprotein that accompanie... more hnRNP A1 is a nucleocytoplasmic shuttling heterogeneous nuclear ribonucleoprotein that accompanies eukaryotic mRNAs from the active site of transcription to that of translation. Although the importance of hnRNP A1 as a regulator of nuclear pre-mRNA and mRNA processing and export is well established, it is unknown whether this is relevant for the control of proliferation, survival, and differentiation of normal and transformed cells. We show here that hnRNP A1 levels are increased in myeloid progenitor cells expressing the p210 BCR/ABL oncoprotein, in mononuclear cells from chronic myelogenous leukemia (CML) blast crisis patients, and during disease progression. In addition, in myeloid progenitor 32Dcl3 cells, BCR/ABL stabilizes hnRNP A1 by preventing its ubiquitin/proteasome-dependent degradation. To assess the potential role of hnRNP A1 nucleocytoplasmic shuttling activity in normal and leukemic myelopoiesis, a mutant defective in nuclear export was ectopically expressed in parental and BCR/ABL-transformed myeloid precursor 32Dcl3

Research paper thumbnail of The Human Immunodeficiency Virus Type 2 Vpx Protein Usurps the CUL4A-DDB1DCAF1 Ubiquitin Ligase To Overcome a Postentry Block in Macrophage Infection

Journal of Virology, 2009

several auxiliary proteins that have increasingly shown their importance in the virus-host relati... more several auxiliary proteins that have increasingly shown their importance in the virus-host relationship. One of these proteins, Vpx, is unique to the HIV-2/SIVsm lineage and is critical for viral replication in macrophages. The functional basis for this requirement, as well as the Vpx mode of action, has remained unexplained, and it is all the more enigmatic that HIV type 1 (HIV-1), which has no Vpx counterpart, can infect macrophages. Here, we underscore DCAF1 as a critical host effector of Vpx in its ability to mediate infection and long-term replication of HIV-2 in human macrophages. Vpx assembles with the CUL4A-DDB1 ubiquitin ligase through DCAF1 recruitment. Precluding Vpx present in the incoming virions from recruiting DCAF1 in target macrophages leads to a postentry block characterized by defective accumulation of HIV-2 reverse transcripts. In addition, Vpx from SIVsm functionally complements Vpx-defective HIV-2 in a DCAF1-binding-dependent manner. Altogether, our data point to a mechanism in which Vpx diverts the Cul4A-DDB1 DCAF1 ligase to inactivate an evolutionarily conserved factor, which restricts macrophage infection by HIV-2 and closely related simian viruses.

Research paper thumbnail of Synergistic effects of cAMP-dependent signalling pathways and IL-1 on IL-6 production by H19-7/IGF-IR neuronal cells

Cellular Signalling, 2006

cAMP-dependent signalling cascades regulate a number of CNS functions including brain inflammatio... more cAMP-dependent signalling cascades regulate a number of CNS functions including brain inflammation processes. In this study, we characterized IL-1-induced IL-6 production in hippocampal cells using H19-7/IGF-IR cells and investigated the effect of changes in intracellular cAMP levels on IL-1 activity. IL-1 potently induced IL-6 mRNA expression with a corresponding increase in IL-6 release, in a time- and dose-dependent manner with a maximal at 24 h and with an EC50 value of 0.11 ng/ml. Cell pre-treatment with the IL-1sR antagonist produced a rightward shift of IL-1 dose-response effect with a corresponding decrease in IL-1 potency. IL-1-induced IL 6 release was attenuated in the presence of the p38 MAPK inhibitor SB203580 but was not significantly affected by the PKA inhibitor KT 5720. Western blotting analysis of phospho-CREB cell content showed a marked increase in CREB activation. Similar results were obtained by pharmacologically increasing cAMP using dibutyryl cyclic adenosine monophosphate (dbcAMP) or the cAMP-specific type-4 phosphodiesterase inhibitor rolipram. Both dbcAMP and rolipram increased IL-6 production to about 50% of IL-1 effect. However, in the presence of IL-1, IL-6 production was further potentiated by either dbcAMP and rolipram, reaching 300% and 500% IL-1-induced levels. These data implicate the role of cAMP-dependent pathways on IL-6 production in neuronal cells and suggest novel synergistic mechanisms of regulation of cytokine production in brain.

Research paper thumbnail of The CDK Inhibitor p21Cip1/WAF1 Is Induced by Fc R Activation and Restricts the Replication of Human Immunodeficiency Virus Type 1 and Related Primate Lentiviruses in Human Macrophages

Journal of Virology, 2009

Research paper thumbnail of PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer

Science translational medicine, Jan 15, 2015

Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER... more Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase α (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of up-regulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on tran...

Research paper thumbnail of Antagonism of EGFR and HER3 Enhances the Response to Inhibitors of the PI3K-Akt Pathway in Triple-Negative Breast Cancer

Science Signaling, 2014

The following resources related to this article are available online at http://stke.sciencemag.org.

Research paper thumbnail of The CDK inhibitor p21Cip1/WAF1 is induced by FcγR activation and restricts HIV-1 replication in human macrophages

Research paper thumbnail of hnRNP A1 Nucleocytoplasmic Shuttling Activity Is Required for Normal Myelopoiesis and BCR/ABL Leukemogenesis

Molecular and Cellular Biology, 2002

hnRNP A1 is a nucleocytoplasmic shuttling heterogeneous nuclear ribonucleoprotein that accompanie... more hnRNP A1 is a nucleocytoplasmic shuttling heterogeneous nuclear ribonucleoprotein that accompanies eukaryotic mRNAs from the active site of transcription to that of translation. Although the importance of hnRNP A1 as a regulator of nuclear pre-mRNA and mRNA processing and export is well established, it is unknown whether this is relevant for the control of proliferation, survival, and differentiation of normal and transformed cells. We show here that hnRNP A1 levels are increased in myeloid progenitor cells expressing the p210 BCR/ABL oncoprotein, in mononuclear cells from chronic myelogenous leukemia (CML) blast crisis patients, and during disease progression. In addition, in myeloid progenitor 32Dcl3 cells, BCR/ABL stabilizes hnRNP A1 by preventing its ubiquitin/proteasome-dependent degradation. To assess the potential role of hnRNP A1 nucleocytoplasmic shuttling activity in normal and leukemic myelopoiesis, a mutant defective in nuclear export was ectopically expressed in parental and BCR/ABL-transformed myeloid precursor 32Dcl3

Research paper thumbnail of The Human Immunodeficiency Virus Type 2 Vpx Protein Usurps the CUL4A-DDB1DCAF1 Ubiquitin Ligase To Overcome a Postentry Block in Macrophage Infection

Journal of Virology, 2009

several auxiliary proteins that have increasingly shown their importance in the virus-host relati... more several auxiliary proteins that have increasingly shown their importance in the virus-host relationship. One of these proteins, Vpx, is unique to the HIV-2/SIVsm lineage and is critical for viral replication in macrophages. The functional basis for this requirement, as well as the Vpx mode of action, has remained unexplained, and it is all the more enigmatic that HIV type 1 (HIV-1), which has no Vpx counterpart, can infect macrophages. Here, we underscore DCAF1 as a critical host effector of Vpx in its ability to mediate infection and long-term replication of HIV-2 in human macrophages. Vpx assembles with the CUL4A-DDB1 ubiquitin ligase through DCAF1 recruitment. Precluding Vpx present in the incoming virions from recruiting DCAF1 in target macrophages leads to a postentry block characterized by defective accumulation of HIV-2 reverse transcripts. In addition, Vpx from SIVsm functionally complements Vpx-defective HIV-2 in a DCAF1-binding-dependent manner. Altogether, our data point to a mechanism in which Vpx diverts the Cul4A-DDB1 DCAF1 ligase to inactivate an evolutionarily conserved factor, which restricts macrophage infection by HIV-2 and closely related simian viruses.

Research paper thumbnail of Synergistic effects of cAMP-dependent signalling pathways and IL-1 on IL-6 production by H19-7/IGF-IR neuronal cells

Cellular Signalling, 2006

cAMP-dependent signalling cascades regulate a number of CNS functions including brain inflammatio... more cAMP-dependent signalling cascades regulate a number of CNS functions including brain inflammation processes. In this study, we characterized IL-1-induced IL-6 production in hippocampal cells using H19-7/IGF-IR cells and investigated the effect of changes in intracellular cAMP levels on IL-1 activity. IL-1 potently induced IL-6 mRNA expression with a corresponding increase in IL-6 release, in a time- and dose-dependent manner with a maximal at 24 h and with an EC50 value of 0.11 ng/ml. Cell pre-treatment with the IL-1sR antagonist produced a rightward shift of IL-1 dose-response effect with a corresponding decrease in IL-1 potency. IL-1-induced IL 6 release was attenuated in the presence of the p38 MAPK inhibitor SB203580 but was not significantly affected by the PKA inhibitor KT 5720. Western blotting analysis of phospho-CREB cell content showed a marked increase in CREB activation. Similar results were obtained by pharmacologically increasing cAMP using dibutyryl cyclic adenosine monophosphate (dbcAMP) or the cAMP-specific type-4 phosphodiesterase inhibitor rolipram. Both dbcAMP and rolipram increased IL-6 production to about 50% of IL-1 effect. However, in the presence of IL-1, IL-6 production was further potentiated by either dbcAMP and rolipram, reaching 300% and 500% IL-1-induced levels. These data implicate the role of cAMP-dependent pathways on IL-6 production in neuronal cells and suggest novel synergistic mechanisms of regulation of cytokine production in brain.

Research paper thumbnail of The CDK Inhibitor p21Cip1/WAF1 Is Induced by Fc R Activation and Restricts the Replication of Human Immunodeficiency Virus Type 1 and Related Primate Lentiviruses in Human Macrophages

Journal of Virology, 2009