Andrew Brooks - Academia.edu (original) (raw)
Papers by Andrew Brooks
Hepatology, 2020
BaCKgRoUND aND aIMS: Growth hormone (GH) is important for liver regeneration after partial hepate... more BaCKgRoUND aND aIMS: Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. appRoaCH aND ReSUltS: PHx was performed on C57BL/6 mice lacking GHR (Ghr −/−), disabled for all GHdependent Janus kinase 2 signaling (Box1 −/−), or lacking only GH-dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391 −/−), and wild-type littermates. C57BL/6 Ghr −/− mice showed striking mortality within 48 hours after PHx, whereas Box1 −/− or Ghr391 −/− mice survived with normal liver regeneration. Ghr −/− mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2-Bl, a key immunotolerance protein, which is up-regulated by PHx through a GH-mediated, Janus kinase 2-independent, SRC family kinase-dependent pathway. GH treatment was confirmed to up-regulate expression of the human homolog of H2-Bl (human leukocyte antigen G [HLA-G]) in primary human hepatocytes and in the serum of GH-deficient patients. We find that injury-associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr −/− mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. Further, H2-Bl knockdown in wild-type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr −/− backcrossed on a strain with high endogenous H2-Bl expression showed a high rate of survival following PHx. CoNClUSIoNS: GH induction of H2-Bl expression is crucial for reducing innate immune-mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA-G may lead to improved clinical outcomes following liver surgery or transplantation. (Hepatology 2020;0:1-17). T he innate immune system has been shown to play a major role in liver regeneration, with key roles being attributed to hepatic natural killer (NK) and natural killer T cells (NKT), the major resident lymphoid cell populations that are located
Expert Review of Endocrinology & Metabolism, 2011
A substantial body of evidence supports a role for the growth hormone (GH)-IGF-1 axis in cancer i... more A substantial body of evidence supports a role for the growth hormone (GH)-IGF-1 axis in cancer incidence and progression. This includes epidemiological evidence relating elevated plasma IGF-1 to cancer incidence as well as a lack of cancers in GH/IGF-1 deficiency. Rodent models lacking GH or its receptor are strikingly resistant to the induction of a wide range of cancers, and treatment with the GH antagonist pegvisomant slows tumor progression. While GH receptor expression is elevated in many cancers, autocrine GH is present in several types, and overexpression of autocrine GH can induce cell transformation. While the mechanism of autocrine action is not clear, it does involve both STAT5 and STAT3 activation, and probably nuclear translocation of the GH receptor. Development of a more potent GH receptor antagonist or secretion inhibitor is warranted for cancer therapy.
Molecular Endocrinology, 2008
The presence of GH receptor (GHR) in the cell nucleus correlates with cell division, and targetin... more The presence of GH receptor (GHR) in the cell nucleus correlates with cell division, and targeting the GHR to the nucleus results in constitutive proliferation and transformation because of increased sensitivity to autocrine GH. Here we have sought additional mechanisms that might account for the enhanced proliferation seen with nuclear GHR, commencing with a yeast two-hybrid (Y2H) screen for interactors with the extracellular domain of the GHR [GH-binding protein (GHBP)]. We find that the GHBP is a transcriptional activator in yeast and mammalian cells, and this activity resides in the lower cytokine receptor module. Activity is dependent on S226, the conserved serine of the cytokine receptor consensus WSXWS box. By using parallel GHBP affinity columns and tandem mass spectrometry of tryptic digests of proteins bound to wild-type GHBP and S226A columns, we identified proteins that bind to the transcriptionally active GHBP. These include a nucleoporin and two transcriptional regulat...
The Journal of infectious diseases, Jan 30, 2015
CD14, a co-receptor for several pattern recognition receptors and a widely used monocyte/macroph... more CD14, a co-receptor for several pattern recognition receptors and a widely used monocyte/macrophage marker, plays a key role in host responses to Gram-negative bacteria. Despite its central role in the inflammatory response to lipopolysaccharide and other microbial products, and in dissemination of bacteria in some infections, the signaling networks controlled by CD14 during urinary tract infection (UTI) are unknown. We used uropathogenic Escherichia coli (UPEC) infection of wild-type (WT) C57BL/6 and Cd14-deficient mice and RNA-sequencing (RNA-seq) to define the CD14-dependent transcriptional signature, and role of CD14, in host defense against UTI in the bladder. UPEC-induced the up-regulation of Cd14 and monocyte/macrophage related genes Emr1/F4/80 and Csf1r/c-fms, which was associated with lower UPEC burdens in WT compared to Cd14-deficient mice. Exacerbation of infection in Cd14-deficient mice was associated with the absence of a 491-gene transcriptional signature in the bla...
Journal of Virology, 2006
Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA-3C) is essential for EBV-mediated immortalizati... more Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA-3C) is essential for EBV-mediated immortalization of human B lymphocytes and regulates both the cell cycle and transcription. Transient reporter gene assays have implicated a pivotal role for EBNA-3C in the regulation of transcription of the majority of latency-associated genes expressed during the EBV growth program, including the viral oncoprotein LMP-1. To examine the regulation of latency gene expression by EBNA-3C, we generated an EBV-positive cell line that inducibly expresses EBNA-3C. This cell line allowed us to examine expression from the endogenous latency gene promoters in the context of an actual latent infection and the presence of other EBNA proteins, in particular EBNA-2, which is presumed to coregulate transcription with EBNA-3C. EBNA-3C induced the expression of both LMP-1 and LMP-2B mRNAs from the bidirectional LMP-1/LMP-2B promoter. In contrast, no effect was seen on expression from the common EBNA promoter Cp, whi...
Endocrine development, 2012
Growth hormone (GH) promotes stem cell activation, cell proliferation, differentiation and surviv... more Growth hormone (GH) promotes stem cell activation, cell proliferation, differentiation and survival, either directly or through the induction of IGF-1. GH acts via its cell membrane receptor to initiate a range of signalling pathways, with JAK2 kinase activation of STAT5 being the most important. The transcription factor STAT5 acts to induce expression of the key growth mediator, IGF-1, but also regulates the expression of a host of other genes, some of which are important growth regulators. In addition to its signalling from the cell membrane, the GH receptor translocates to the nucleus in a GH-dependent manner, where it regulates the expression of other cell growth-related genes, and sensitises the cell to the proliferative action of GH.
Hepatology, 2020
BaCKgRoUND aND aIMS: Growth hormone (GH) is important for liver regeneration after partial hepate... more BaCKgRoUND aND aIMS: Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. appRoaCH aND ReSUltS: PHx was performed on C57BL/6 mice lacking GHR (Ghr −/−), disabled for all GHdependent Janus kinase 2 signaling (Box1 −/−), or lacking only GH-dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391 −/−), and wild-type littermates. C57BL/6 Ghr −/− mice showed striking mortality within 48 hours after PHx, whereas Box1 −/− or Ghr391 −/− mice survived with normal liver regeneration. Ghr −/− mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2-Bl, a key immunotolerance protein, which is up-regulated by PHx through a GH-mediated, Janus kinase 2-independent, SRC family kinase-dependent pathway. GH treatment was confirmed to up-regulate expression of the human homolog of H2-Bl (human leukocyte antigen G [HLA-G]) in primary human hepatocytes and in the serum of GH-deficient patients. We find that injury-associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr −/− mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. Further, H2-Bl knockdown in wild-type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr −/− backcrossed on a strain with high endogenous H2-Bl expression showed a high rate of survival following PHx. CoNClUSIoNS: GH induction of H2-Bl expression is crucial for reducing innate immune-mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA-G may lead to improved clinical outcomes following liver surgery or transplantation. (Hepatology 2020;0:1-17). T he innate immune system has been shown to play a major role in liver regeneration, with key roles being attributed to hepatic natural killer (NK) and natural killer T cells (NKT), the major resident lymphoid cell populations that are located
Expert Review of Endocrinology & Metabolism, 2011
A substantial body of evidence supports a role for the growth hormone (GH)-IGF-1 axis in cancer i... more A substantial body of evidence supports a role for the growth hormone (GH)-IGF-1 axis in cancer incidence and progression. This includes epidemiological evidence relating elevated plasma IGF-1 to cancer incidence as well as a lack of cancers in GH/IGF-1 deficiency. Rodent models lacking GH or its receptor are strikingly resistant to the induction of a wide range of cancers, and treatment with the GH antagonist pegvisomant slows tumor progression. While GH receptor expression is elevated in many cancers, autocrine GH is present in several types, and overexpression of autocrine GH can induce cell transformation. While the mechanism of autocrine action is not clear, it does involve both STAT5 and STAT3 activation, and probably nuclear translocation of the GH receptor. Development of a more potent GH receptor antagonist or secretion inhibitor is warranted for cancer therapy.
Molecular Endocrinology, 2008
The presence of GH receptor (GHR) in the cell nucleus correlates with cell division, and targetin... more The presence of GH receptor (GHR) in the cell nucleus correlates with cell division, and targeting the GHR to the nucleus results in constitutive proliferation and transformation because of increased sensitivity to autocrine GH. Here we have sought additional mechanisms that might account for the enhanced proliferation seen with nuclear GHR, commencing with a yeast two-hybrid (Y2H) screen for interactors with the extracellular domain of the GHR [GH-binding protein (GHBP)]. We find that the GHBP is a transcriptional activator in yeast and mammalian cells, and this activity resides in the lower cytokine receptor module. Activity is dependent on S226, the conserved serine of the cytokine receptor consensus WSXWS box. By using parallel GHBP affinity columns and tandem mass spectrometry of tryptic digests of proteins bound to wild-type GHBP and S226A columns, we identified proteins that bind to the transcriptionally active GHBP. These include a nucleoporin and two transcriptional regulat...
The Journal of infectious diseases, Jan 30, 2015
CD14, a co-receptor for several pattern recognition receptors and a widely used monocyte/macroph... more CD14, a co-receptor for several pattern recognition receptors and a widely used monocyte/macrophage marker, plays a key role in host responses to Gram-negative bacteria. Despite its central role in the inflammatory response to lipopolysaccharide and other microbial products, and in dissemination of bacteria in some infections, the signaling networks controlled by CD14 during urinary tract infection (UTI) are unknown. We used uropathogenic Escherichia coli (UPEC) infection of wild-type (WT) C57BL/6 and Cd14-deficient mice and RNA-sequencing (RNA-seq) to define the CD14-dependent transcriptional signature, and role of CD14, in host defense against UTI in the bladder. UPEC-induced the up-regulation of Cd14 and monocyte/macrophage related genes Emr1/F4/80 and Csf1r/c-fms, which was associated with lower UPEC burdens in WT compared to Cd14-deficient mice. Exacerbation of infection in Cd14-deficient mice was associated with the absence of a 491-gene transcriptional signature in the bla...
Journal of Virology, 2006
Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA-3C) is essential for EBV-mediated immortalizati... more Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA-3C) is essential for EBV-mediated immortalization of human B lymphocytes and regulates both the cell cycle and transcription. Transient reporter gene assays have implicated a pivotal role for EBNA-3C in the regulation of transcription of the majority of latency-associated genes expressed during the EBV growth program, including the viral oncoprotein LMP-1. To examine the regulation of latency gene expression by EBNA-3C, we generated an EBV-positive cell line that inducibly expresses EBNA-3C. This cell line allowed us to examine expression from the endogenous latency gene promoters in the context of an actual latent infection and the presence of other EBNA proteins, in particular EBNA-2, which is presumed to coregulate transcription with EBNA-3C. EBNA-3C induced the expression of both LMP-1 and LMP-2B mRNAs from the bidirectional LMP-1/LMP-2B promoter. In contrast, no effect was seen on expression from the common EBNA promoter Cp, whi...
Endocrine development, 2012
Growth hormone (GH) promotes stem cell activation, cell proliferation, differentiation and surviv... more Growth hormone (GH) promotes stem cell activation, cell proliferation, differentiation and survival, either directly or through the induction of IGF-1. GH acts via its cell membrane receptor to initiate a range of signalling pathways, with JAK2 kinase activation of STAT5 being the most important. The transcription factor STAT5 acts to induce expression of the key growth mediator, IGF-1, but also regulates the expression of a host of other genes, some of which are important growth regulators. In addition to its signalling from the cell membrane, the GH receptor translocates to the nucleus in a GH-dependent manner, where it regulates the expression of other cell growth-related genes, and sensitises the cell to the proliferative action of GH.