140 research outputs found
Discovery and Characterization of an Endogenous CXCR4 Antagonist
CXCL12-CXCR4 signaling controls multiple physiological
processes and its dysregulation is associated
with cancers and inflammatory diseases. To
discover as-yet-unknown endogenous ligands of
CXCR4, we screened a blood-derived peptide library
for inhibitors of CXCR4-tropic HIV-1 strains.
This approach identified a 16 amino acid fragment
of serum albumin as an effective and highly specific
CXCR4 antagonist. The endogenous peptide, termed
EPI-X4, is evolutionarily conserved and generated
from the highly abundant albumin precursor by
pH-regulated proteases. EPI-X4 forms an unusual
lasso-like structure and antagonizes CXCL12-induced
tumor cell migration, mobilizes stem cells,
and suppresses inflammatory responses in mice.
Furthermore, the peptide is abundant in the urine
of patients with inflammatory kidney diseases and
may serve as a biomarker. Our results identify EPIX4
as a key regulator of CXCR4 signaling and introduce
proteolysis of an abundant precursor protein
as an alternative concept for chemokine receptor
regulation
ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phosholipase C gamma 1 and protein kinase C pathways
This work was supported by the German Research Foundation DFG (SFB 850/B6) and by the Fritz-Thyssen
foundation (Az.10.14.2.150) to C.-W.F and the Medical Research Council (MR/L010402/1) to D.P.K
Characterization of ductal and lobular breast carcinomas using novel prolactin receptor isoform specific antibodies
<p>Abstract</p> <p>Background</p> <p>Prolactin is a polypeptide hormone responsible for proliferation and differentiation of the mammary gland. More recently, prolactin's role in mammary carcinogenesis has been studied with greater interest. Studies from our laboratory and from others have demonstrated that three specific isoforms of the prolactin receptor (PRLR) are expressed in both normal and cancerous breast cells and tissues. Until now, reliable isoform specific antibodies have been lacking. We have prepared and characterized polyclonal antibodies against each of the human PRLR isoforms that can effectively be used to characterize human breast cancers.</p> <p>Methods</p> <p>Rabbits were immunized with synthetic peptides of isoform unique regions and immune sera affinity purified prior to validation by Western blot and immunohistochemical analyses. Sections of ductal and lobular carcinomas were stained with each affinity purified isoform specific antibody to determine expression patterns in breast cancer subclasses.</p> <p>Results</p> <p>We show that the rabbit antibodies have high titer and could specifically recognize each isoform of PRLR. Differences in PRLR isoform expression levels were observed and quantified using histosections from xenografts of established human breast cancer cells lines, and ductal and lobular carcinoma human biopsy specimens. In addition, these results were verified by real-time PCR with isoform specific primers. While nearly all tumors contained LF and SF1b, the majority (76%) of ductal carcinoma biopsies expressed SF1a while the majority of lobular carcinomas lacked SF1a staining (72%) and 27% had only low levels of expression.</p> <p>Conclusions</p> <p>Differences in the receptor isoform expression profiles may be critical to understanding the role of PRL in mammary tumorigenesis. Since these antibodies are specifically directed against each PRLR isoform, they are valuable tools for the evaluation of breast cancer PRLR content and have potential clinical importance in treatment of this disease by providing new reagents to study the protein expression of the human PRLR.</p
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