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1.
Biochem Biophys Res Commun ; 454(4): 537-42, 2014 11 28.
Article in English | MEDLINE | ID: mdl-25450689

ABSTRACT

Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (adisintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti-inflammatory corticosteroids as well as 1,25-(OH)2D3, a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-α receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion.


Subject(s)
Integrins/metabolism , Lymphocytes/cytology , Lymphocytes/drug effects , Retinoic Acid Receptor alpha/agonists , Retinoic Acid Receptor alpha/metabolism , Retinoids/pharmacology , Cell Adhesion/drug effects , Dose-Response Relationship, Drug , Humans , Lymphocytes/metabolism , Structure-Activity Relationship
2.
J Nutr Biochem ; 24(5): 832-41, 2013 May.
Article in English | MEDLINE | ID: mdl-22925918

ABSTRACT

Retinoids are essential in the proper establishment and maintenance of immunity. Although retinoids are implicated in immune related processes, their role in immune cell adhesion has not been well established. In this study, the effect of 9-cis-retinoic acid (9-cis-RA) on human hematopoietic cell adhesion was investigated. 9-cis-RA treatment specifically induced cell adhesion of the human immune cell lines HuT-78, NB4, RPMI 8866 and U937. Due to the prominent role of integrin receptors in mediating immune cell adhesion, we sought to evaluate if cell adhesion was integrin-dependent. By employing a variety of integrin antagonist including function-blocking antibodies and EDTA, we establish that 9-cis-RA prompts immune cell adhesion through established integrin receptors in addition to a novel integrin-independent process. The novel integrin-independent adhesion required the presence of retinoid and was attenuated by treatment with synthetic corticosteroids. Finally, we demonstrate that 9-cis-RA treatment of primary murine B-cells induces ex vivo adhesion that persists in the absence of integrin function. Our study is the first to demonstrate that 9-cis-RA influences immune cell adhesion through at least two functionally distinct mechanisms.


Subject(s)
Antineoplastic Agents/pharmacology , B-Lymphocytes/cytology , Cell Adhesion/drug effects , Integrins/metabolism , Tretinoin/pharmacology , Adrenal Cortex Hormones/metabolism , Alitretinoin , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Cell Differentiation/drug effects , Cell Line , Flow Cytometry , Humans , Mice , Mice, Inbred C57BL , Receptors, Retinoic Acid/genetics , Receptors, Retinoic Acid/metabolism , Recombinant Fusion Proteins
3.
J Cell Physiol ; 227(3): 1235-41, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21688267

ABSTRACT

The Ras-ERK/MAP (Mitogen-Activated Protein) kinase signaling pathway governs many cellular processes such as proliferation, differentiation, cell fate, homeostasis, and survival in all eukaryotes. Constitutive activation of the Ras-ERK/MAPK signaling pathway often leads to promotion of abnormal cell growth and tumorigenesis. Although the regulation of the Ras-ERK/MAPK signaling pathway by post-translational modification has been well elucidated, post-transcriptional regulations of this pathway are beginning to emerge in invertebrates and this work is extended to humans. In this review, we describe the conserved regulation of Ras-ERK/MAPK signaling by RNA-binding proteins (PUF, KH-domain, HuR, and LARP) and microRNAs (let-7 family miRNAs) and important implications for human diseases including cancers.


Subject(s)
Extracellular Signal-Regulated MAP Kinases/genetics , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinases/genetics , RNA-Binding Proteins/physiology , Transcription, Genetic/physiology , ras Proteins/genetics , Extracellular Signal-Regulated MAP Kinases/biosynthesis , Humans , MAP Kinase Signaling System/genetics , Mitogen-Activated Protein Kinases/biosynthesis , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/metabolism , RNA-Binding Proteins/genetics , ras Proteins/biosynthesis
4.
J Cell Biochem ; 107(5): 992-1001, 2009 Aug 01.
Article in English | MEDLINE | ID: mdl-19479935

ABSTRACT

Prostate tumorigenesis is associated with loss of PTEN gene expression. We and others have recently reported that PTEN is regulated by Notch-1 signaling. Herein, we tested the hypothesis that alterations of the Notch-1 signaling pathway are present in human prostate adenocarcinoma and that Notch-1 signaling regulates PTEN gene expression in prostate cells. Prostate adenocarcinoma cases were examined by immunohistochemistry for ligand cleaved (activated) Notch-1 protein. Tumor foci exhibited little cleaved Notch-1 protein, but expression was observed in benign tissue. Both tumor and benign tissue expressed total (uncleaved) Notch-1. Reduced Hey-1 expression was seen in tumor foci but not in benign tissue, confirming loss of Notch-1 signaling in prostate adenocarcinoma. Retroviral expression of constitutively active Notch-1 in human prostate tumor cell lines resulted in increased PTEN gene expression. Incubation of prostate cell lines with the Notch-1 ligand, Delta, resulted in increased PTEN expression indicating that endogenous Notch-1 regulates PTEN gene expression. Chromatin immunoprecipitation demonstrated that CBF-1 was bound to the PTEN promoter. These data collectively indicate that defects in Notch-1 signaling may play a role in human prostate tumor formation in part via a mechanism that involves regulation of the PTEN tumor suppressor gene.


Subject(s)
Gene Expression Regulation, Neoplastic , PTEN Phosphohydrolase/genetics , Prostatic Neoplasms/enzymology , Prostatic Neoplasms/genetics , Receptors, Notch/metabolism , Signal Transduction , Cell Line, Tumor , Cell Movement , Humans , Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism , Male , PTEN Phosphohydrolase/metabolism , Promoter Regions, Genetic/genetics , Prostatic Neoplasms/pathology , Protein Binding , Transcriptional Activation/genetics
5.
Cell Cycle ; 6(1): 80-4, 2007 Jan 01.
Article in English | MEDLINE | ID: mdl-17245125

ABSTRACT

The PTEN gene regulates multiple signaling pathways that influence cell proliferation, survival and differentiation. Loss of PTEN expression is closely linked with oncogenesis. Little is known regarding regulation of PTEN gene expression. The PTEN promoter region has been reported and is regulated in part by p53. In a previous study, we found that Notch-1 signaling resulted in increased PTEN protein expression. Herein, we tested the hypothesis that the PTEN gene is a direct target of Notch-1 signal transduction, through binding of the Notch-activated transcription factor CBF-1 to the PTEN minimal promoter. 293 cells expressing constitutively active Notch-1 exhibited increased PTEN gene expression and promoter transactivation. Overexpression of CBF-1 in 293 cells resulted in decreased PTEN gene expression. Mobility shift assays and supershift assays demonstrated that CBF-1 binds to the PTEN minimal promoter. These data indicate that the Notch-1 receptor pathway is a key regulator of PTEN gene transcription.


Subject(s)
Gene Expression Regulation/physiology , Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism , PTEN Phosphohydrolase/metabolism , Promoter Regions, Genetic/physiology , Base Sequence , Cell Line , Humans , Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics , Molecular Sequence Data , PTEN Phosphohydrolase/biosynthesis , PTEN Phosphohydrolase/genetics , Protein Binding/genetics
6.
Br J Haematol ; 135(4): 438-49, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16965385

ABSTRACT

Mixed lineage leukaemia gene-partial tandem duplications (MLL-PTD) characterise acute myeloid leukaemia (AML) with trisomy 11 and AML with a normal karyotype. MLL-PTD confer a worse prognosis with shortened overall and event free survival in childhood and adult AML. In spite of these clinical observations, the leukaemogenic mechanism has, so far, not been determined. This review summarises clinical studies on MLL-PTD positive AML and recent experimental findings on the putative leukaemogenic role of MLL-PTD.


Subject(s)
Gene Duplication , Leukemia, Myeloid/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Tandem Repeat Sequences , Acute Disease , Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 11/genetics , DNA, Neoplasm/genetics , Genetic Predisposition to Disease , Histone-Lysine N-Methyltransferase , Humans , Prognosis , Trisomy
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