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1.
Oncotarget ; 6(28): 26308-21, 2015 Sep 22.
Article in English | MEDLINE | ID: mdl-26299618

ABSTRACT

Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation. We also show that the Ser291-phosphorylated form of the multifunctional protein and stem cell marker, CD44, inhibits FBXO21-directed degradation of P-gp. Thus, CD44 increases P-gp mediated drug resistance and represents a potential therapeutic target in P-gp-positive cells.


Subject(s)
Drug Resistance, Multiple , Drug Resistance, Neoplasm , F-Box Proteins/metabolism , Hyaluronan Receptors/metabolism , Ubiquitination , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Animals , BALB 3T3 Cells , Drug Resistance, Multiple/genetics , Drug Resistance, Neoplasm/genetics , F-Box Proteins/genetics , Female , Humans , Hyaluronan Receptors/genetics , MCF-7 Cells , Mice , Phosphorylation , Proteasome Endopeptidase Complex/metabolism , Protein Binding , Protein Stability , Proteolysis , RNA Interference , Serine , Time Factors , Transfection , Two-Hybrid System Techniques
2.
J Biol Chem ; 287(23): 18995-9007, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-22433859

ABSTRACT

CD44 is a multifunctional cell receptor that conveys a cancer phenotype, regulates macrophage inflammatory gene expression and vascular gene activation in proatherogenic environments, and is also a marker of many cancer stem cells. CD44 undergoes sequential proteolytic cleavages that produce an intracytoplasmic domain called CD44-ICD. However, the role of CD44-ICD in cell function is unknown. We take a major step toward the elucidation of the CD44-ICD function by using a CD44-ICD-specific antibody, a modification of a ChIP assay to detect small molecules, and extensive computational analysis. We show that CD44-ICD translocates into the nucleus, where it then binds to a novel DNA consensus sequence in the promoter region of the MMP-9 gene to regulate its expression. We also show that the expression of many other genes that contain this novel response element in their promoters is up- or down-regulated by CD44-ICD. Furthermore, hypoxia-inducible factor-1α (Hif1α)-responsive genes also have the CD44-ICD consensus sequence and respond to CD44-ICD induction under normoxic conditions and therefore independent of Hif1α expression. Additionally, CD44-ICD early responsive genes encode for critical enzymes in the glycolytic pathway, revealing how CD44 could be a gatekeeper of the Warburg effect (aerobic glycolysis) in cancer cells and possibly cancer stem cells. The link of CD44 to metabolism is novel and opens a new area of research not previously considered, particularly in the study of obesity and cancer. In summary, our results finally give a function to the CD44-ICD and will accelerate the study of the regulation of many CD44-dependent genes.


Subject(s)
Cell Nucleus/metabolism , Hyaluronan Receptors/metabolism , Matrix Metalloproteinase 9/biosynthesis , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Neoplastic Stem Cells/metabolism , Response Elements , Transcription, Genetic , Active Transport, Cell Nucleus , Cell Nucleus/genetics , Cell Nucleus/pathology , Female , Glycolysis/genetics , Humans , Hyaluronan Receptors/genetics , Matrix Metalloproteinase 9/genetics , Neoplasm Proteins/genetics , Neoplasms/genetics , Neoplasms/pathology , Neoplastic Stem Cells/pathology , Protein Structure, Tertiary
3.
J Eukaryot Microbiol ; 55(6): 522-9, 2008.
Article in English | MEDLINE | ID: mdl-19120798

ABSTRACT

Strains of the opportunistic fungal pathogen Candida albicans vary in the presence or absence of a self-splicing group I intron ribozyme (Ca.LSU) in the 25S rRNA gene on chromosome R. Strains of C. albicans typically either lack or contain this ribozyme. However, some strains have both intron-containing and intronless rRNA genes (rDNA). Pulsed-field gel electrophoresis analysis of undigested and restricted DNA showed at least six different karyotypes among eight independent colonies of such a heteroallelic strain. In each case, the variation was in chromosome R, and was due to changes in the number of rDNA units. In strains with only one type of rDNA, chromosome R also varied considerably. Polymerase chain reaction amplification spanning the rDNA unit demonstrated that intron-containing rDNA units are tandemly arrayed, and are immediately adjacent to intronless units in the same cluster. Both types of units were present in the rDNA clusters of both R chromosomes. Possible explanations of these results are loss of Ca.LSU group I intron through purifying selection and/or a relaxation of the commonly accepted concerted evolution of the rDNA units.


Subject(s)
Candida albicans/genetics , DNA, Fungal/genetics , DNA, Ribosomal/genetics , Chromosomes, Fungal/genetics , Introns , RNA, Ribosomal/genetics
4.
Mol Cancer Res ; 4(8): 511-20, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16908592

ABSTRACT

Chronic inflammation is implicated in the pathophysiology of ovarian cancer. Tumor necrosis factor-alpha (TNF-alpha), a major inflammatory cytokine, is abundant in the ovarian cancer microenvironment. TNF-alpha modulates the expression of CD44 in normal T lymphocytes and CD44 is implicated in ovarian carcinogenesis and metastases. However, little is known about the role of TNF-alpha in CD44 expression of cancer cells. Recent clinical work using TNF-alpha inhibitors for the treatment of ovarian cancer makes the study of TNF-alpha interactions with CD44 crucial to determining treatment a success or a failure. We studied the effect of TNF-alpha on ovarian cancer cells viability, CD44 expression, and in vitro migration/invasion. Our results revealed that TNF-alpha differentially modulates the expression of CD44 in TNF-alpha-resistant ovarian cancer cells, affecting their in vitro migration, invasion, and binding to hyaluronic acid. TNF-alpha up-regulation of CD44 expression was dependent on the activation of c-Jun NH(2)-terminal kinase (JNK) and this activation was accompanied by an increase in their invasive phenotype. On the contrary, if TNF-alpha failed to induce JNK phosphorylation, the end result was down-regulation of both CD44 expression and the invasive phenotype. These results were confirmed by the use of JNK inhibitors and a TNF receptor competitive inhibitor.


Subject(s)
Gene Expression Regulation, Neoplastic/drug effects , Hyaluronan Receptors/metabolism , Ovarian Neoplasms/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Cell Proliferation/drug effects , Cell Survival/drug effects , Collagen/drug effects , Drug Combinations , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Hyaluronic Acid/metabolism , Laminin/drug effects , Neoplasm Invasiveness , Proteoglycans/drug effects , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/metabolism
5.
Cancer Res ; 65(15): 6660-7, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-16061646

ABSTRACT

Invasion and metastases of cancer cells and the development of resistance to anticancer therapies are the main causes of morbidity and mortality from cancer. For more than two decades, these two important but not clearly related aspects in the biology of cancer have been extensively studied. Specifically, P-glycoprotein and CD44 have been characterized and are known to be determinants of multidrug resistance (MDR) and metastases. Despite this body of knowledge, few reports have linked the two phenotypes and only recently have there been reasons to suspect a direct connection. In this report, we show that a novel physical and genetic interaction between CD44s and P-glycoprotein is in part responsible for the correlation between MDR and invasive potential in cancer cells. P-glycoprotein-specific substrates that interfere with its function reduced in vitro invasion, migration, and the physical colocalization of CD44s and P-glycoprotein. CD44 expression in sensitive cells promoted the expression of P-glycoprotein and the MDR phenotype. RNA interference of MDR1 inhibited the rate of cell migration. These data indicate that there is a close interaction between CD44 and P-glycoprotein that results in the concurrent expression and modulation of two malignant phenotypes, invasion and MDR.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Cell Movement/physiology , Hyaluronan Receptors/metabolism , Neoplasms/metabolism , Neoplasms/pathology , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Cell Line, Tumor , Cell Membrane/metabolism , Cell Movement/drug effects , Drug Resistance, Neoplasm , Female , Flupenthixol/pharmacology , Humans , Hyaluronan Receptors/biosynthesis , Hyaluronan Receptors/genetics , Immunoprecipitation , Neoplasm Invasiveness , Neoplasms/drug therapy , RNA Interference , Transfection
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