Variety Of Integrins Research Articles

Functional consequences of inhibition of Bruton's tyrosine kinase by ibrutinib in chronic lymphocytic leukemia.

The leukemic B cells from patients with chronic lymphocytic leukemia (CLL) require interactions with non-malignant cells and matrix in the tissue microenvironment to survive and grow. These interactions are mediated through the B-cell antigen receptor (BCR), C-X-C chemokine receptor type 4 (CXCR4), and a variety of integrins, including VLA-4. Exciting each receptor type leads to activation of Bruton's tyrosine kinase (BTK), which in turn helps initiate trophic signals that prevent cell death and promote cell activation and growth as well as allowing cells to return to anatomic sites for rescue signals. These represent the two major functional actions targeted by inhibitors of Btk. Here we relate some of the therapeutic actions of ibrutinib, a Btk inhibitor that is extremely helpful for patients with CLL, certain Diffuse Large B-cell Lymphomas (ABC type), and other non-Hodgkin's lymphomas, emphasizing that ibrutinib's value results from blocking beneficial signals, not by inducing lethal ones.

The role of the CCN family of proteins in female reproduction.

The CCN family of proteins consists of six high homologous matricellular proteins which act predominantly by binding to heparin sulphate proteoglycan and a variety of integrins. Interestingly, CCN proteins are regulated by ovarian steroid hormones and are able to adapt to changes in oxygen concentration, which is a necessary condition for successful implantation. CCN1 is involved in processes of angiogenesis within reproductive systems, thereby potentially contributing to diseases such as endometriosis and disturbed angiogenesis in the placenta and fetus. In the ovary, CCN2 is the key factor for follicular development, ovulation and corpora luteal luteolysis, and its deletion leads to fertility defects. CCN1, CCN2 and CCN3 seem to be regulators for human trophoblast proliferation and migration, but with CCN2 acting as a counterweight. Alterations in the expression of these three proteins could contribute to the shallow invasion properties observed in preeclampsia. Little is known about the role of CCN4-6 in the reproductive organs. The ability of CCN1, CCN2 and CCN3 to interact with numerous receptors enables them to adapt their biological function rapidly to the continuous remodelling of the reproductive organs and in the development of the placenta. The CCN proteins mediate their specific cell physiological function through the receptor type of their binding partner followed by a defined signalling cascade. Because of their partly overlapping expression patterns, they could act in a concert synergistically or in an opposite way within the reproductive organs. Imbalances in their expression levels are correlated to different human reproductive diseases, such as endometriosis and preeclampsia.

Development and Characterization of Endothelial Cells from Rat Microlymphatics

The lymphatic endothelium is important to the functioning of the lymphatic system, including lymphatic remodeling, control of vessel tone, and lymphatic movement of fluids, macromolecules, and cells. Many of these events occur principally at the level of the microlymphatics. To evaluate the role of the microlymphatic endothelium, a suitable cultured cell line would be useful. We have developed a technique to isolate and culture endothelial cells from microscopic lymphatics, approximately 100 microm in diameter. To isolate the rat mesenteric lymphatic endothelial cells (RMLEC), the rat was anesthetized and the mesentery carefully exteriorized. A suitable microlymphatic was located and carefully microdissected from the surrounding mesentery. The vessel was carefully cleaned, cannulated, everted, and then incubated on a gelatin-coated plastic culture dish until small patches of cells migrated off of the vessel (3-4 days later.) The explanted vessel was then removed. The remaining cells were cultured and screened for endothelial phenotype. Nonendothelial cells were destroyed. The endothelial nature of the remaining cells was verified by: 1) morphology, 2) uptake of fluorescent acetylated-LDL, 3) staining for von Wille-brand factor, PECAM-1, ecNOS, LYVE-1, VEGFR-3, and 4) essentially negative alpha-vascular smooth muscle actin staining. The defined RMLEC were passed and the profile of adhesion molecules present on the RMLEC was then determined using PCR and immunofluorescence. We developed and partially characterized a line of cultured microlymphatic endothelium. RMLEC express known endothelial- and lymphatic-specific markers as well as the following adhesion molecules: N-cadherin, E-cadherin, PECAM-1, alpha-catenin, beta-catenin, gamma-catenin, p120, and a variety of integrins.

Design, synthesis and biological evaluation of nonpeptide integrin antagonists

Recent studies demonstrated that peptide and antibody antagonists of integrin α vβ 3 block angiogenesis and tumor growth. In this article, the design, synthesis and biological evaluation of a series of nitroaryl ether-based, nonpeptide mimetics are described. The design of these compounds was based on Merck’s arylether/α-aminoacid/guanidine framework and incorporates a novel nitroaryl system. The synthesized mimetics were tested against a variety of integrins (α vβ 3, α IIbβ 3, and α vβ 5) in order to determine their binding selectivity and ability to inhibit cell adhesion. Selected compounds were also tested for their ability to inhibit angiogenesis in vivo in the CAM (chick chorioallantoic membrane) assay. From the generated compound library, compounds 16 and 19 proved to be potent and selective inhibitors of α IIbβ 3 (IC 50=14 nM) whereas compound 11 showed excellent in vivo inhibition of angiogenesis (at 30 μg/embryo).

Differential mRNA regulation of integrin subunits alpha V, beta 1, beta 3, and beta 5 during mouse embryonic organogenesis.

Cell interactions with extracellular matrices play important roles in morphogenetic processes during embryonic development. Extracellular matrix receptors of the integrin family have been implicated in these steps. Recent studies indicate that a variety of integrins can be differentially expressed during development, consistent with diverse roles for integrins in embryogenesis. The present study compares the expression patterns of several major members of the alpha V integrin subfamily, focusing on mRNA expression of alpha V, beta 1, beta 3, and beta 5 subunits during mouse embryonic organogenesis using Northern blot analysis and in situ hybridization. The alpha V and beta 1 subunits showed widespread tissue expression, although most tissues expressed alpha V at relatively low or basal levels. The mRNA for beta 5 was also expressed in a variety of embryonic organs and showed unusual localization patterns in certain organs. Striking, high-level expression of beta 5 transcripts was detected in the ependymal layer of the central nervous system, glomeruli of the kidney, epicardial region of the heart, and in the tooth germs, suggesting specific functions for this molecule during morphogenetic events in these organs. In contrast, few beta 3 transcripts were expressed during mid-gestation mouse embryogenesis except in megakaryocytes within the embryonic liver. These observations of differing expression spectra suggest that members of the alpha V integrin subfamily have distinct roles and also suggests that they have different transcriptional regulation. The beta 5 integrin is unique in its degree of tissue-specific mRNA regulation associated with morphogenesis of embryonic organs.