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Kevin P Rosenblatt

Publications and source records attributed to Kevin P Rosenblatt.

8 recordsLinked to original sources
PubMed2006

Regulation of fibroblast growth factor-23 signaling by klotho.

The aging suppressor gene Klotho encodes a single-pass transmembrane protein. Klotho-deficient mice exhibit a variety of aging-like phenotypes, many of which are similar to those observed in fibroblast growth factor-23 (FGF23)-deficient mice. To test the possibility that Klotho and FGF23 may function in a common signal transduction pathway(s), we investigated whether Klotho is involved in FGF signaling. Here we show that Klotho protein directly binds to multiple FGF receptors (FGFRs). The Klotho-FGFR complex binds to FGF23 with higher affinity than FGFR or Klotho alone. In addition, Klotho significantly enhanced the ability of FGF23 to induce phosphorylation of FGF receptor substrate and ERK in various types of cells. Thus, Klotho functions as a cofactor essential for activation of FGF signaling by FGF23.

Animals↗
PubMed2005

Regulation of oxidative stress by the anti-aging hormone klotho.

klotho is an aging suppressor gene and extends life span when overexpressed in mice. Klotho protein was recently demonstrated to function as a hormone that inhibits insulin/insulin-like growth factor-1 (IGF-1) signaling. Here we show that Klotho protein increases resistance to oxidative stress at the cellular and organismal level in mammals. Klotho protein activates the FoxO forkhead transcription factors that are negatively regulated by insulin/IGF-1 signaling, thereby inducing expression of manganese superoxide dismutase. This in turn facilitates removal of reactive oxygen species and confers oxidative stress resistance. Thus, Klotho-induced inhibition of insulin/IGF-1 signaling is associated with increased resistance to oxidative stress, which potentially contributes to the anti-aging properties of klotho.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Suppression of aging in mice by the hormone Klotho.

A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.

Aging↗
PubMed2005

Pathology of the future: molecular profiling for targeted therapy.

Recent evidence suggests that each patient's cancer has a unique subset of molecular pathogenetic derangements. These derangements may both genetic and proteomic alterations. Genomic and proteomic research tools enable genome-wide assessment of gene expression as well as kinase driven cell signaling events. These tools are illuminating the molecular derangements of individual tumors, even if these tumors have similar morphological characteristics. A combination of laser capture microdissection with multiplexed phosphoproteomic analysis using reverse phase protein microarray technology is being used to identify protein molecular signatures of individual tumors. The in vivo state of multiple kinase driven signal pathways may be evaluated by reverse phase protein microarray with a panel of specific antibodies developed based upon our knowledge of biological processes. Molecular profiling of individual patient's tumors is currently being evaluated in clinical trials at the National Institutes of Health, National Cancer Institute for monitoring Epidermal Growth Factor (EGF) cell signaling events for patients with breast and ovarian cancer.

Forecasting↗
PubMed2004

Generation and analysis of melanoma SAGE libraries: SAGE advice on the melanoma transcriptome.

In this study, we generated three SAGE libraries from melanoma tissues. Using bioinformatics tools usually applied to microarray data, we identified several genes, including novel transcripts, which are preferentially expressed in melanoma. SAGE results converged with previous microarray analysis on the importance of intracellular calcium and G-protein signaling, and the Wnt/Frizzled family. We also examined the expression of CD74, which was specifically, albeit not abundantly, expressed in the melanoma libraries using a melanoma progression tissue microarray, and demonstrate that this protein is expressed by melanoma cells but not by benign melanocytes. Many genes involved in intracellular calcium and G-protein signaling were highly expressed in melanoma, results we had observed earlier from microarray studies (Bittner et al., 2000). One of the genes most highly expressed in our melanoma SAGE libraries was a calcium-regulated gene, calpain 3 (p94). Immunohistochemical analysis demonstrated that calpain 3 moves from the nuclei of non-neoplastic cells to the cytoplasm of malignant cells, suggesting activation of this intracellular proteinase. Our SAGE results and the clinical validation data demonstrate how SAGE profiles can highlight specific links between signaling pathways as well as associations with tumor progression. This may provide insights into new genes that may be useful for the diagnosis and therapy of melanoma.

Aged↗
PubMed2004

Serum proteomics in cancer diagnosis and management.

Mass spectrometry-based diagnostics has the potential to revolutionize molecular medicine. Using modern mass-spectrometer technologies, clinical tests can be developed that are practical, robust, accurate, and inexpensive. Serum proteomic pattern profiling couples mass spectrometry with adaptive artificial-intelligence-based bioinformatics, which can now be employed to detect pathological states reflected in the serum proteome. With this approach, rapid and cost-effective tests with exquisite clinical sensitivity and specificity are emerging. These tools may dramatically change how disease is detected, monitored, and managed.

Blood Proteins↗
PubMedDate not supplied

Pegylated, steptavidin-conjugated quantum dots are effective detection elements for reverse-phase protein microarrays.

Protein microarray technologies provide a means of investigating the proteomic content of clinical biopsy specimens in order to determine the relative activity of key nodes within cellular signaling pathways. A particular kind of protein microarray, the reverse-phase microarray, is being evaluated in clinical trials because of its potential to utilize limited amounts of cellular material obtained through biopsy. Using this approach, cellular lysates are arrayed in dilution curves on nitrocellulose substrates for subsequent probing with antibodies. To improve the sensitivity and utility of reverse-phase microarrays, we tested whether a new reporter technology as well as a new detection instrument could enhance microarray performance. We describe the use of an inorganic fluorescent nanoparticle conjugated to streptavidin, Qdot 655 Sav, in a reverse-phase protein microarray format for signal pathway profiling. Moreover, a pegylated form of this bioconjugate, Qdot 655 Sav, is found to have superior detection characteristics in assays performed on cellular protein extracts over the nonpegylated form of the bioconjugate. Hyperspectral imaging of the quantum dot microarray enabled unamplified detection of signaling proteins within defined cellular lysates, which indicates that this approach may be amenable to multiplexed, high-throughput reverse-phase protein microarrays in which numerous analytes are measured in parallel within a single spot.

Calibration↗