Robert J. Lefkowitz

Bio: Robert J. Lefkowitz is an academic researcher from Howard Hughes Medical Institute. The author has contributed to research in topics: Receptor & G protein-coupled receptor. The author has an hindex of 214, co-authored 860 publications receiving 147995 citations. Previous affiliations of Robert J. Lefkowitz include University of Nice Sophia Antipolis & University of Stuttgart.

Characterization of alpha 2-adrenergic receptor subtype-specific antibodies.

Abstract: Subtypes of alpha 2-adrenergic receptors have been defined pharmacologically in a variety of mammalian tissues. The alpha 2A, alpha 2B, alpha 2C, and most recently alpha 2D subtypes have been characterized by their affinities for selective receptor antagonists and agonists. The genes that may encode the alpha 2A, alpha 2B, and alpha 2C subtypes have been identified in human and rat. In human these genes are termed alpha 2-C10, alpha 2-C2, and alpha 2-C4, respectively, based on their chromosomal localization, whereas three genes, designated RG20 alpha 2, RNG alpha 2, and RG10 alpha 2, are thought to be the corresponding rat homologues. These assignments were based on the pharmacology of the cloned receptor genes expressed in transfected cells and on the detection of homologous mRNAs by Northern blot analyses in cell lines or tissues with pharmacologically defined alpha 2-adrenergic receptors. However, the subtype assignment of cloned genes has not been fully resolved by these means. To help clarify the subtype assignment, we have raised antibodies against sequences from the divergent third intracellular loop of the human and rat alpha 2-adrenergic receptors. These antibodies were found to be subtype specific in immunoprecipitating either the cloned receptors expressed by DNA transfection or the pharmacologically defined receptors prepared from various tissues. Our immunological data corroborate the assignments of alpha 2-C2/RNG alpha 2 as encoding the alpha 2B subtype in NG108-15 cells and rat neonatal lung and of alpha 2-C4/RG10 alpha 2 as encoding the alpha 2C subtype in opossum kidney cells. Furthermore, antibodies against alpha 2-C10 and RG20 alpha 2 but not alpha 2-C2/RNG alpha 2 or alpha 2-C4/RG10 alpha 2 were both found to recognize alpha 2-adrenergic receptors expressed in rat submaxillary glands and in bovine pineal gland, two tissues with alpha 2D pharmacology. Because three genes were identified in the rat and human genome, these data suggest that the pharmacologically defined "alpha 2D receptor" is genetically of the alpha 2A subtype.

β-Arrestin2 mediates the initiation and progression of myeloid leukemia.

Abstract: β-Arrestins were initially discovered as negative regulators of G protein-coupled receptor signaling. Although β-arrestins have more recently been implicated as scaffold proteins that interact with various mitogenic and developmental signals, the genetic role of β-arrestins in driving oncogenesis is not known. Here we have investigated the role of β-arrestin in hematologic malignancies and have found that although both β-arrestin1 and -2 are expressed in the hematopoietic system, loss of β-arrestin2 preferentially leads to a severe impairment in the establishment and propagation of the chronic and blast crisis phases of chronic myelogenous leukemia (CML). These defects are linked to a reduced frequency, as well as defective self-renewal capacity of the cancer stem-cell population, in mouse models and in human CML patient samples. At a molecular level, the loss of β-arrestin2 leads to a significant inhibition of β-catenin stabilization, and ectopic activation of Wnt signaling reverses the defects observed in the β-arrestin2 mutant cells. These data cumulatively show that β-arrestin2 is essential for CML disease propagation and indicate that β-arrestins and the Wnt/β-catenin pathway lie in a signaling hierarchy in the context of CML cancer stem cell maintenance.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans

Abstract: Experimental introduction of RNA into cells can be used in certain biological systems to interfere with the function of an endogenous gene Such effects have been proposed to result from a simple antisense mechanism that depends on hybridization between the injected RNA and endogenous messenger RNA transcripts RNA interference has been used in the nematode Caenorhabditis elegans to manipulate gene expression Here we investigate the requirements for structure and delivery of the interfering RNA To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually After injection into adult animals, purified single strands had at most a modest effect, whereas double-stranded mixtures caused potent and specific interference The effects of this interference were evident in both the injected animals and their progeny Only a few molecules of injected double-stranded RNA were required per affected cell, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Abstract: The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)