144 research outputs found
Estrogen and TCDD Influence RLN2 Gene Activity in Estrogen Receptor-Positive Human Breast Cancer Cells
No full textExpression of relaxin is increased in human breast cancer, and relaxin was shown to increase in vitro invasiveness through increased production and secretion of matrix metalloproteinases in human breast cancer cells. The role of estrogen in the promotion of breast cancer is well-known. The environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen but has been shown to have antiestrogenic effects in human breast cancer cells. In this study, we have employed real-time PCR and chromatin immunoprecipitation (ChIP) assays to investigate the influence of estrogen and TCDD on relaxin-1 (RLN1) and relaxin-2 (RLN2) gene expression in MCF-7 and T47D human breast cancer cells. Estrogen increased RLN2 transcripts in T47D and MCF-7 cells after just 4 h of exposure, whereas TCDD did not. RLN1 transcripts were only induced after 24 h of estrogen exposure. TCDD did have antiestrogenic activity and reduced the estrogen-mediated increase in RLN2 and RLN1 mRNA. The estrogen-mediated increase in RLN2 mRNA levels was not caused by changes in the mRNA stability. ChIP analysis revealed binding of estrogen receptor-alpha (ER alpha) to promoter sequences of the RLN2 gene. Thus, we provide evidence that RLN2 gene activity is directly regulated by activated ERa in human breast cancer cells and we show that activation of the arylhydrocarbon receptor by TCDD inhibits this regulation by estrogen
INSL5-Deficient Mice Display an Alteration in Glucose Homeostasis and an Impaired Fertility
No full textInsulin-like factor 5 (INSL5), a member of the insulin superfamily, is expressed in the colorectum and hypothalamus. To facilitate studies into the role of INSL5, we generated Insl5(-/-) mice by gene targeting. Insl5(-/-) mice were born in the expected Mendelian ratio, reached normal body weight, but displayed impaired male and female fertility that are due to marked reduction in sperm motility and irregular length of the estrous cycle. Furthermore, Insl5(-/-) mice showed impairment in glucose homeostasis with characteristic elevation of serum glucose levels at an advanced age. Glucose and insulin tolerance tests revealed that the increased blood glucose in Insl5(-/-) mice was due to glucose intolerance resulting from reduced insulin secretion. Morphometric and immunohistological analyses revealed that the Insl5(-/-) mice had markedly reduced average islets area and beta-cell numbers. Furthermore, immunohistochemistry showed the expression of INSL5 in enteroendocrine cells in the colorectal epithelium and the presence of its putative receptor relaxin family peptide receptor 4 in pancreatic islet cells. These results suggest the potential role of INSL5 signaling in the regulation of insulin secretion and beta-cell homeostasis. (Endocrinology 153: 4655-4665, 2012
INSL5 is a novel marker for human enteroendocrine cells of the large intestine and neuroendocrine tumours
No full textWe report for the first time the distribution of human INSL5 and its cognate leucine rich G-protein coupled receptor RXFP4 in the large intestine and in neuroendocrine/carcinoid tissues. Immunoreactive INSL5 was uniquely expressed by enteroendocrine cells (EECs) located within the colonic mucosa, whereas colonocytes were immunopositive for RXFP4. INSL5(+) and RXFP4(+) cells were also detected in human neuroendocrine/carcinoid tissues. We employed a recently described Insl5 knockout mouse model and 2 mouse models of induced colitis to address the relevance of Insl5 in EEC development and in acute inflammation of the colon. We identified INSL5 as a specific marker for synaptophysin(+) EECs in the mucosa of the normal human and mouse colon. Insl5 was not essential for the development of mouse synaptophysin(+) EECs. The mouse models of chemically induced colitis (dextran sulfate sodium and dinitrobenzene-sulfonic acid) failed to show changes in the numbers of Insl5(+) EECs at inflammatory sites during the acute phase of colitis. In conclusion, we showed that INSL5 is a novel marker of colorectal EECs and provide first evidence for the presence of a potentially autocrine/paracrine INSL5-RXFP4 signaling system in the normal human and mouse colon and in rare human neuroendocrine tumours
Comparative aspects of relaxin and relaxin-like factor (Insulin 3) in the placental trophoblast
No full textA mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis
No full textHyaluronidases are endoglycosidases that hydrolyze hyaluronan (HA), an abundant component of the extracellular matrix of vertebrate connective tissues. Six human hyaluronidase-related genes have been identified to date. Mutations in one of these genes cause a deficiency of hyaluronidase 1 (HYAL1) resulting in a lysosomal storage disorder, mucopolysaccharidosis (MPS) IX. We have characterized a mouse model of MPS IX and compared its phenotype with the human disease. The targeted Hyal1 allele in this model had a neomycin resistance cassette in exon 2 that replaced 753 bp of the coding region containing the predicted enzyme active site. As a result, Hyal1-/- animals had no detectable wild-type Hyal1 transcript, protein or serum activity. Hyal1 null animals were viable, fertile and showed no gross abnormalities at 1 year and 8 months of age. Histological studies of the knee joint showed a loss of proteoglycans occurring as early as 3 months that progressed with age. An increased number of chondrocytes displaying intense pericellular and/or cytoplasmic HA staining were detected in the epiphyseal and articular cartilage of null mice, demonstrating an accumulation of HA. Elevations of HA were not detected in the serum or non-skeletal tissues, indicating that osteoarthritis is the key disease feature in a Hyal1 deficiency. Hyal3 expression was elevated in Hyal1 null mice, suggesting that Hyal3 may compensate in HA degradation in non-skeletal tissues. Overall, the murine MPS IX model displays the key features of the human disease.Dianna C. Martin, Vasantha Atmuri, Richard J. Hemming, Judith Farley, John S. Mort, Sharon Byers, Sabine Hombach-Klonisch, Robert Stern and Barbara L. Triggs-Rain
Extracellular S100A4 induces human thyroid cancer cell migration
No full textHuman thyroid cancer is the most commonly occurring cancer of the endocrine gland having good survival rate, but some patients show recurrence with an invasive phenotype and treatment failures. The mechanisms behind this invasive phenotype are not well understood in TC. Previously our group has identified a pro-migratory role of relaxin-like peptides in thyroid cancer that is mediated by S100A4. We have observed in human TC cells that extracellular S100A4 induces migration and activates ERK1/2, JNK/SAPK and NFkB signaling pathways. Employing immunohistochemistry and immunofluorescence we have identified the expression of RAGE in human TC primary cells, cell lines, and in tumor tissues but not in normal thyroid tissues. We showed that S100A4 binds to RAGE in TC cells and that RAGE and its cytoplasmic partner Dia-1 mediate the S100A4-induced migration of TC cells. This study identified a crucial role of RAGE in TC cell migration induced by S100A4.October 201
E-cadherin, catenin, cytoskeletal interactions and induced pluripotency
No full textPluripotency is defined as the capability of cells to differentiate into cell types derived from each of the three embryonic germ layers (Kelly et al., 2011). Induced pluripotency defines a process of epigenetic reprogramming in which epigenetic changes implemented during differentiation are reversed to generate cells with a stem-like phenotype. Fibroblasts (Takahashi and Yamanaka, 2006; Sommer et al., 2009), human keratinocytes (Aasen et al., 2008) and nasal mucosal cells (Ono et al., 2012) can be reprogrammed to stem-like cells with introduction of four stem cell transcription factors Oct4, KLF4, Sox2 and c-Myc (OKSM). Previous studies have provided evidence that the adhesion and cellular signaling provided by a glycoprotein, known as E-cadherin, has essential functions in pluripotency. Induced pluripotency has potential medical application which the induced pluripotent stem cells (iPSCs) apply as clinical tools for modeling diseases, drug development, and to deliver cell-replacement therapy to support regenerative medicine (Goldthwaite, 2011).The present review summarizes our current knowledge on the role of E-cadherin, its cellular signaling and cytoskeletal interactions in the induction and maintenance of pluripotent cells
Emerging roles of High Mobility Group A (HMGA) family members in nuclear organization.
No full textChromatin remodeling plays a crucial role in gene expression. Chromatin architecture is governed by the interaction of a variety of proteins and transcription factors, including histones and non-histone chromatin-binding factors. Non-histone proteins, such as high mobility group-associated proteins (HMGA), are key players in this process. They do not have transcriptional activity per se but comprise flexible intrinsically disordered proteins (IDP) which interact with nucleosomes to change the compaction of chromatin at enhancers and promoters, thereby modulating the process of transcription. HMGA proteins have attained significant attention for their role in the regulation of gene expression during development, cell differentiation and in cellular senescence. Their molecular interactions are controlled by posttranslational modifications which determine nucleoprotein complex formation and function. This review highlights the role of HMGA proteins in nuclear organization, at telomeres and centromere regions and in senescence-associated heterochromatin foci (SAHF) and links these spatiotemporal chromatin architectural functions to the molecular domain structure of HMGA proteins in fine-tuning dynamic chromatin states.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
HMGA2 Inhibits Apoptosis through Interaction with ATR-CHK1 Signaling Complex in Human Cancer Cells
No full textAbstractThe non-histone chromatin binding protein high mobility group AT-hook 2 (HMGA2) is expressed in stem cells and many cancer cells, including tumor initiating cells, but not translated in normal human somatic cells. The presence of HMGA2 is correlated with advanced neoplastic disease and poor prognosis for patients. We had previously demonstrated a role of HMGA2 in DNA repair pathways. In the present study, we employed different human tumor cell models with endogenous and exogenous expression of HMGA2 and show that upon DNA damage, the presence of HMGA2 caused an increased and sustained phosphorylation of the ataxia telangiectasia and Rad3-related kinase (ATR) and its downstream target checkpoint kinase 1 (CHK1). The presence of activated pCHK1Ser296 coincided with prolonged G2/M block and increased tumor cell survival, which was enhanced further in the presence of HMGA2. Our study, thus, identifies a novel relationship between the ATR-CHK1 DNA damage response pathway and HMGA2, which may support the DNA repair function of HMGA2 in cancer cells. Furthermore, our data provide a rationale for the use of inhibitors to ATR or CHK1 and HMGA2 in the treatment of HMGA2-positive human cancer cells
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