Author
Robert J. Lefkowitz
Other affiliations: University of Nice Sophia Antipolis, University of Stuttgart, Laboratory of Molecular Biology ...read more
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.
Papers published on a yearly basis
Papers
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20 Dec 1993TL;DR: In this article, a recombinant cell comprising a host cell containing recombinant DNA sequence is disclosed, and in vitro assays employing the foregoing which are useful for screening test compounds for antitumor and antiatherogenic activity, along with a diagnostic assay for detecting the oncogenic activation of cells in a patient.
Abstract: A recombinant cell comprising a host cell containing a recombinant DNA sequence is disclosed. The recombinant DNA sequence comprises vector DNA and DNA which encodes a mammalian adrenergic receptor. The host cell is one capable of undergoing proliferation in response to activation of the adrenergic receptor. In one specific embodiment of the foregoing, the adrenergic receptor includes a mutation in the third cytoplasmic loop thereof which renders the adrenergic receptor constitutively active, and the host cell undergoes proliferation in response to the constitutively active adrenergic receptor. Also disclosed are in vitro assays employing the foregoing which are useful for screening test compounds for antitumor and antiatherogenic activity, along with a diagnostic assay for detecting the oncogenic activation of cells in a patient. The diagnostic assay comprises collecting sample cells which express adrenergic receptors from the patient, and then detecting the presence or absence of a mutation in the adrenergic receptor which renders the receptor constitutively active. The presence of such a mutation indicates the oncogenic activation of the cells.
6 citations
01 Jan 2000
TL;DR: Data reveal that PSD-95 is a specific b1AR binding partner that modulates b1ar function and facilitates physical association of the b1 AR with synaptic proteins, such as the N-methyl-Daspartate receptors, which are known to be regulated by b1Ar stimulation.
Abstract: The b1-adrenergic receptor (b1AR) is the most abundant subtype of b-adrenergic receptor in the mammalian brain and is known to potently regulate synaptic plasticity. To search for potential neuronal b1AR-interacting proteins, we screened a rat brain cDNA library using the b1AR carboxyl terminus (b1AR-CT) as bait in the yeast two-hybrid system. These screens identified PSD-95, a multiple PDZ domain-containing scaffolding protein, as a specific binding partner of the b1AR-CT. This interaction was confirmed by in vitro fusion protein pull-down and blot overlay experiments, which demonstrated that the b1AR-CT binds specifically to the third PDZ domain of PSD-95. Furthermore, the full-length b1AR associates with PSD-95 in cells, as determined by co-immunoprecipitation experiments and immunofluorescence co-localization studies. The interaction between b1AR and PSD-95 is mediated by the last few amino acids of the b1AR, and mutation of the b1AR carboxyl terminus eliminated the binding and disrupted the co-localization of the b1AR and PSD-95 in cells. Agonist-induced internalization of the b1AR in HEK-293 cells was markedly attenuated by PSD-95 co-expression, whereas co-expression of PSD-95 has no significant effect on either desensitization of the b1AR or b1AR-induced cAMP accumulation. Furthermore, PSD-95 facilitated the formation of a complex between the b1AR and N-methyl-D-aspartate receptors, as assessed by co-immunoprecipitation. These data reveal that PSD-95 is a specific b1AR binding partner that modulates b1AR function and facilitates physical association of the b1AR with synaptic proteins, such as the N-methyl-Daspartate receptors, which are known to be regulated by b1AR stimulation.
6 citations
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TL;DR: This year's Presidential Address to the American Society for Clinical Investigation was delivered with inspiration while reviewing the stated objectives of the Society, as set forth in its constitution written eighty years ago in 1908.
Abstract: Members and guests. It is for me a very great honor and privilege to deliver this year's Presidential Address to the American Society for Clinical Investigation. As I pondered over what approach I would take, my mind drifted back to previous such addresses that I had heard. In fact, this is the 20th consecutive such oration at which I have been present. What, I have repeatedly asked myself, could I possibly add to the sage comments of my predecessors? As I thought about this I came to realize the highly personal nature of these commentaries in terms of both style and content. Each has been informed by the unique perspective of the President and shaped, of course, by the nature of his academic activities at the time. For example, several who have chaired departments have discussed the future ofthe physician scientist, while another focused on the key role of the department chair in promoting clinical investigation. Others who had been particularly active in the public sector have concentrated on the interfaces between the biomedical research community and governmental agencies and funding sources. Two recent presidents who had also served as Editors of the Journal of Clinical Investigation discussed peer review and fraud in science, respectively. But I have not chaired a department, led a division, organized a formal training program , or edited the Journal of Clinical Investigation. Rather, for the past twenty years I have largely devoted my professional activities to the scientific life and the associated activity oftrying to nurture various young scientists who have come to work with me. Given that this is my perspective, what should be my sub-ject? I found my inspiration while reviewing the stated objectives of our Society, as set forth in its constitution written eighty years ago in 1908. Five objectives were listed: (a) the advancement of medical science; (b) the cultivation of clinical research by the methods of the natural sciences; (c) the correlation of science with the art of medical practice; (d) the encouragement of scientific investigation by the medical practitioner ; and (e) the diffusion of a scientific spirit among its [the Society's] members. This last I believe to be the most important. So apparently did our Founders, since they listed only two obligations of membership: to attend the annual meeting at least every other Address reprint requests to Dr. year and to \"further the objectives of the society …
5 citations
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TL;DR: It is indicated that lack of antiapoptotic βarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L and that βarr 2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.
Abstract: Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, β-arrestin2 (βarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between βarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor βarr2-knockout (βarr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted βarr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of βarr2-/- cells. In order to assess the effect of acute loss of βarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional βarr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic βarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that βarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.
5 citations
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03 Oct 1997TL;DR: In this article, a method of inhibiting arterial and venous smooth muscle proliferation resulting from arterial injury or vein grafting was proposed, and an expression construct encoding a Gβη inhibitor suitable for use in such a method.
Abstract: The present invention relates, in general, to vascular smooth muscle proliferation and, in particular, to a method of inhibiting arterial and venous smooth muscle proliferation resulting, for example, from arterial injury or vein grafting. The invention also relates to an expression construct encoding a Gβη inhibitor suitable for use in such a method.
5 citations
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组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�ly.
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。
18,940 citations
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TL;DR: To their surprise, it was found that double-stranded RNA was substantially more effective at producing interference than was either strand individually, arguing against stochiometric interference with endogenous mRNA and suggesting that there could be a catalytic or amplification component in the interference process.
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
15,374 citations
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TL;DR: This approach provides two major advantages compared with other available methods: it uses an exact mathematical model of the ligand-binding system, thereby avoiding the possible biases introduced by several commonly used approximations and it uses a statistically valid, appropriately weighted least-squares curve-fitting algorithm with objective measurement of goodness of fit.
8,717 citations
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TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
7,056 citations
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TL;DR: This review considers recent findings regarding GC action and generates criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stress-response or, as an additional category, is preparative for a subsequent stressor.
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)
6,707 citations