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Direct progesterone receptor and indirect androgen receptor interactions with the kallikrein-related peptidase 4 gene promoter in breast and prostate cancer

- Lai, John, Myers, Stephen, Lawrence, Mitchell, Odorico, Dimitri, Clements, Judith

  • Authors: Lai, John , Myers, Stephen , Lawrence, Mitchell , Odorico, Dimitri , Clements, Judith
  • Date: 2009
  • Type: Text , Journal article
  • Relation: Molecular Cancer Research Vol. 7, no. 1 (2009), p. 129-141
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  • Description: Kallikrein 4 (KLK4) is a member of the human KLK gene family of serine proteases, many of which are implicated in hormone-dependent cancers. Like other KLKs, such as KLK3/PSA and KLK2, KLK4 gene expression is also regulated by steroid hormones in hormone-dependent cancers, although the transcriptional mechanisms are ill defined. Here, we have investigated the mechanisms mediating the hormonal regulation of KLK4 in breast (T47D) and prostate (LNCaP and 22Rv1) cancer cells. We have shown that KLK4 is only expressed in breast and prostate cancers that express the progesterone receptor (PR) and androgen receptor (AR), respectively. Expression analysis in PR- and AR-positive cells showed that the two predominant KLK4 variants that use either TIS1 or TIS2a/b are both up-regulated by progesterone in T47D cells and androgens in LNCaP cells. Two putative hormone response elements, K4.pPRE and K4.pARE at -2419 bp and -1005 bp, respectively, were identified in silico. Electrophoretic mobility shift assays and luciferase reporter experiments suggest that neither K4.pARE nor ∼2.8 kb of the KLK4 promoter interacts directly with the AR to mediate KLK4 expression in LNCaP and 22Rv1 cells. However, we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. Further, chromatin immunoprecipitation experiments showed a time-dependent recruitment of the PR to the KLK4 promoter (-2496 to -2283), which harbors K4.pPRE. This is the first study to show that progesterone- regulated KLK4 expression in T47D cells is mediated partly by a hormone response element (K4.pPRE) at -2419 bp. (Mol Cancer Res 2009;7(1):129-41)Copyright © 2009 American Association for Cancer Research.

Testing the NKT cell hypothesis in lenalidomide-treated myelodysplastic syndrome patients

- Chan, Angela, Neeson, Paul, Leeansyah, Edwin, Tainton, K., Quach, Hang, Prince, Henry, Godfrey, Dale, Ritchie, David, Berzins, Stuart

  • Authors: Chan, Angela , Neeson, Paul , Leeansyah, Edwin , Tainton, K. , Quach, Hang , Prince, Henry , Godfrey, Dale , Ritchie, David , Berzins, Stuart
  • Date: 2010
  • Type: Text , Journal article
  • Relation: Leukemia Vol. 24, no. 3 (2010), p. 592-600
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  • Description: Myelodysplastic syndrome (MDS) comprises a group of clonal bone marrow disorders characterized by ineffective hematopoiesis and increased predisposition to acute myeloid leukemia. The causes of MDS remain poorly defined, but several studies have reported the NKT cell compartment of patients with MDS is deficient in number and functionally defective. In support of a central role for NKT cells, a pilot clinical study reported that lenalidomide (an approved treatment for MDS) increased NKT cell numbers in patients with MDS, and several in vitro studies showed lenalidomide specifically promoted NKT cell proliferation and cytokine production. We tested this in a much larger study and confirm a moderate in vitro augmentation of some NKT cell functions by lenalidomide, but find no impact on the NKT cell compartment of patients treated with lenalidomide, despite a consistently positive clinical response. We further show that the frequency and cytokine production of NKT cells is normal in patients with MDS before treatment and remains stable throughout 10 months of lenalidomide therapy. Collectively, our data challenge the concept that NKT cell defects contribute to the development of MDS, and show that a clinical response to lenalidomide is not dependent on modulation of NKT cell frequency or function. © 2010 Macmillan Publishers Limited All rights reserved.

Lamin A/C-dependent interaction with 53BP1 promotes cellular responses to DNA damage

- Gibbs-Seymour, Ian, Markiewicz, Ewa, Bekker-Jensen, Simon, Mailand, Niels, Hutchison, Chris

  • Authors: Gibbs-Seymour, Ian , Markiewicz, Ewa , Bekker-Jensen, Simon , Mailand, Niels , Hutchison, Chris
  • Date: 2015
  • Type: Text , Journal article
  • Relation: Aging Cell Vol. 14, no. 2 (2015), p. 162-169
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  • Description: Lamins A/C have been implicated in DNA damage response pathways. We show that the DNA repair protein 53BP1 is a lamin A/C binding protein. In undamaged human dermal fibroblasts (HDF), 53BP1 is a nucleoskeleton protein. 53BP1 binds to lamins A/C via its Tudor domain, and this is abrogated by DNA damage. Lamins A/C regulate 53BP1 levels and consequently lamin A/C-null HDF display a 53BP1 null-like phenotype. Our data favour a model in which lamins A/C maintain a nucleoplasmic pool of 53BP1 in order to facilitate its rapid recruitment to sites of DNA damage and could explain why an absence of lamin A/C accelerates aging. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

A time to kill : Viral manipulation of the cell death program

- Hay, Stewart, Kannourakis, George

  • Authors: Hay, Stewart , Kannourakis, George
  • Date: 2002
  • Type: Text , Journal article
  • Relation: Journal of General Virology Vol. 83, no. 7 (2002), p. 1547-1564
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  • Description: Many viruses have as part of their arsenal the ability to modulate the apoptotic pathways of the host. It is counter-intuitive that such simple organisms would be efficient at regulating this the most crucial pathway within the host, given the relative complexity of the host cells. Yet, viruses have the potential to initiate or stay the onset of programmed cell death through the manipulation of a variety of key apoptotic proteins. It is the intention of this review to provide an overview of viral gene products that are able to promote or inhibit apoptotic death of the host cell and to discuss their mechanisms of action. It is not until recently that the depth at which viruses exploit the apoptotic pathways of their host has been seen. This understanding may provide a great opportunity for future therapeutic ventures.
  • Description: 2003000164

The glucocorticoid receptor 1A3 promoter correlates with high sensitivity to glucocorticoid-induced apoptosis in human lymphocytes

- Liddicoat, Douglas, Kyparissoudis, Konstantinos, Berzins, Stuart, Cole, Timothy, Godfrey, Dale

  • Authors: Liddicoat, Douglas , Kyparissoudis, Konstantinos , Berzins, Stuart , Cole, Timothy , Godfrey, Dale
  • Date: 2014
  • Type: Text , Journal article
  • Relation: Immunology and Cell Biology Vol. 92, no. 10 (2014), p. 825-836
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  • Description: Glucocorticoids (GCs) are powerful inhibitors of inflammation and immunity. Although glucocorticoid-induced cell death (GICD) is an important part of GCs actions, the cell types and molecular mechanisms involved are not well understood. Untranslated exon 1A3 of the human glucocorticoid receptor (GR) gene is a major determinant of GICD in GICD-sensitive human cancer cell lines, operating to dynamically upregulate GR levels in response to GCs. We measured the GICD sensitivity of freshly isolated peripheral blood mononuclear cells and thymocytes to dexamethasone in vitro, relating this to GR exon 1A3 expression. A clear GICD sensitivity hierarchy was detected: B cells>thymocytes/natural killer (NK) cells>peripheral T cells. Within thymocyte populations, GICD sensitivity decreased with maturation. Interestingly, NK cell subsets were differentially sensitive to GICD, with CD16 + CD56 int (cytotoxic) NK cells being highly resistant to GICD, whereas CD16-CD56 hi (cytokine producing) NK cells were highly sensitive (similar to B cells). B-cell GICD was rescued by co-culture with interleukin-4. Strikingly, although no significant increases in GR protein were observed during 48 h of culture of GICD-sensitive and-resistant cells alike, GR 1A3 expression was increased over pre-culture levels in a manner directly proportional to the GICD sensitivity of each cell type. Accordingly, this is the first evidence that the GR exon 1A3 promoter is differentially regulated during thymic development and maturation of human T cells. Furthermore, human peripheral blood B cells are exquisitely GICD-sensitive in vitro, giving new insight into how GCs may downregulate immunity. Collectively, these data show that GR 1A3 expression is tied with GICD sensitivity in human lymphocytes, underscoring the potential for GR 1A3 expression to be used as a biomarker for sensitivity to GICD. © 2014 Australasian Society for Immunology Inc.

Ex-vivo analysis of human Natural Killer T cells demonstrates heterogeneity between tissues and within established CD4+ and CD4- subsets

- Chan, Angela, Leeansyah, Edwin, Cochrane, Andrew, d'Udekem, Yves, Mittag, Diana, Harrison, Leonard, Godfrey, Dale, Berzins, Stuart

  • Authors: Chan, Angela , Leeansyah, Edwin , Cochrane, Andrew , d'Udekem, Yves , Mittag, Diana , Harrison, Leonard , Godfrey, Dale , Berzins, Stuart
  • Date: 2013
  • Type: Text , Journal article
  • Relation: Clinical and Experimental Immunology Vol. 172, no. 1 (2013), p. 129-137
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  • Description: Summary: Our understanding of human type 1 natural killer T (NKT) cells has been heavily dependent on studies of cells from peripheral blood. These have identified two functionally distinct subsets defined by expression of CD4, although it is widely believed that this underestimates the true number of subsets. Two recent studies supporting this view have provided more detail about diversity of the human NKT cells, but relied on analysis of NKT cells from human blood that had been expanded in vitro prior to analysis. In this study we extend those findings by assessing the heterogeneity of CD4+ and CD4- human NKT cell subsets from peripheral blood, cord blood, thymus and spleen without prior expansion ex vivo, and identifying for the first time cytokines expressed by human NKT cells from spleen and thymus. Our comparative analysis reveals highly heterogeneous expression of surface antigens by CD4+ and CD4- NKT cell subsets and identifies several antigens whose differential expression correlates with the cytokine response. Collectively, our findings reveal that the common classification of NKT cells into CD4+ and CD4- subsets fails to reflect the diversity of this lineage, and that more studies are needed to establish the functional significance of the antigen expression patterns and tissue residency of human NKT cells. © 2012 British Society for Immunology.
  • Description: 2003010856
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