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Jeffrey S. Rubin, M.D., Ph.D.

Portait Photo of Jeffrey Rubin
Laboratory of Cellular and Molecular Biology
Senior Investigator
Center for Cancer Research
National Cancer Institute
Building 37, Room 2066
Bethesda, MD 20892-4256
Phone:  
301-496-4265
Fax:  
301-496-8479
E-Mail:  
rubinj@mail.nih.gov

Biography

Dr. Rubin received his M.D. and Ph.D. in molecular biology from Washington University, St. Louis, MO, in 1983. Following an internal medicine residency program at the Jewish Hospital of St. Louis, he joined the Laboratory of Cellular and Molecular Biology at the NCI in 1986 as a biotechnology fellow, where he is now a senior investigator. Dr. Rubin has served as a reviewer for many scientific journals, notably as an editorial board member of the Journal of Biological Chemistry, 1998-2003.

Research

Initial studies: KGF and HGF

From 1986-1996 my research primarily dealt with the purification and biological activities of two heparin-binding mitogens, keratinocyte growth factor (KGF, also known as FGF-7) and hepatocyte growth factor (HGF). These proteins are mediators of mesenchymal-epithelial communication; they stimulate cell migration, differentiation, proliferation and tissue morphogenesis. Through collaborative projects, we explored the role of these factors in development, tissue repair, reproductive tract biology and neoplasia. Investigation by many laboratories demonstrated remarkable cytoprotective effects of KGF that contribute to the maintenance of epithelial barrier function. Palifermin, a recombinant modified version of KGF, was shown in a series of clinical trials to decrease the incidence and duration of severe oral mucositis in patients receiving intensive cancer treatment prior to peripheral blood progenitor cell transplantation for hematologic malignancies. Based on this study, in 2004 the U.S. Food and Drug Administration approved palifermin for use in this setting. Additional trials have been conducted to test its ability to decrease the incidence and duration of severe oral mucositis in patients with solid tumors. Other groups have been exploring its potential to facilitate immune reconstitution following peripheral blood progenitor cell transplantation.

Wnt Signaling and Secreted Frizzled-Related Protein

My group has been working in the Wnt field for the past 15 years since we purified secreted Frizzled-related protein 1 (sFRP1) and identified it as a Wnt antagonist. Subsequently, we showed that it bound directly to Wnt protein and had biphasic effects on Wnt signaling. For the past few years the primary goal of sFRP research has been the identification of factors responsible for its potentiation vs. inhibition of Wnt3a/β-catenin signaling. Cell context is a major factor: biphasic activity was observed in HEK293 cells (potentiation at 1-10 nM sFRP1, inhibition at 100-300 nM), potentiation was predominant in C57MG mammary epithelial cells, while only inhibition was evident in L929 fibroblasts. Receptor expression is another key factor as ectopic expression of Fzd5, but not Fzd2, in L929 cells enabled sFRP1 to enhance Wnt3a activity in the β-catenin pathway.

The R-spondins comprise another family of secreted proteins that regulate Wnt signaling. Recently we reported that R-spondin2 enhanced the up- and down-regulation of Wnt3a target genes in C57MG mouse mammary epithelial cells. Several novel target genes were identified and validated by quantitative PCR. Whereas increases in gene expression were dependent on β-catenin, Wnt3a and Rspo2 rapidly down-regulated a subset of genes by a process that was blocked by the β-catenin pathway antagonist Dickkopf 1, but not by β-catenin siRNA knockdown, implying that a new β-catenin-independent mechanism may be responsible for this regulation.

Casein Kinase 1 Delta

During the last 5 years we have become interested in the dramatic changes in cell shape induced by Wnts. We developed an Ewing sarcoma family of tumor (ESFT) cell model to study the mechanisms of Wnt3a-dependent neurite outgrowth, and demonstrated that neurite extension was mediated by the Wnt receptor Frizzled 3 (Fzd3), Dishevelled 2 and 3 (Dvl2/3) and c-Jun amino-terminal kinase. Neurite outgrowth correlated with Dvl phosphorylation, which was attributed to the activity of casein kinase 1 delta (CK1δ) and epsilon (CK1ε). Knockdown of CK1δ, but not CK1ε, inhibited Wnt3a-dependent neurite outgrowth. Their contrasting activities were associated with differences in their intracellular distribution: CK1δ preferentially localized to the centrosome, an organelle involved in neurite formation. We mapped the centrosomal localization signal to a portion of the C-terminal domain and established that the centrosomal localization of CK1δ was critical for Wnt3a-dependent neurite extension.

Using ciliogenesis as a prime example, we have tested the hypothesis that CK1δ is required for other cellular processes that depend on the centrosome. Results from several models have confirmed this idea. Mechanistic analysis suggests that CK1δ affects ciliogenesis in many ways, both in the centrosomal/ pericentrosomal area and the Golgi. Our results indicate that CK1δ regulates ciliary transport, and the intracellular distribution of other proteins known to participate in ciliogenesis. Our research objectives now focus on defining the function of CK1δ in ciliogenesis, with an emphasis on mechanisms that involve MT nucleation and vesicle trafficking.

This page was last updated on 4/23/2014.