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Richard Martin

Publications and source records attributed to Richard Martin.

6 recordsLinked to original sources
PubMed2003

Unsuspected role of the brain morphogenetic gene Otx1 in hematopoiesis.

Otx1 belongs to the paired class of homeobox genes and plays a pivotal role in brain development. Here, we show that Otx1 is expressed in hematopoietic pluripotent and erythroid progenitor cells. Moreover, bone marrow cells from mice lacking Otx1 exhibit a cell-autonomous impairment of the erythroid compartment. In agreement with these results, molecular analysis revealed decreased levels of erythroid genes that include the SCL and GATA-1 transcription factors. Accordingly, a gain of function of SCL rescues the erythroid deficiency in Otx1-/- mice. Taken together, our findings indicate a function for Otx1 in the regulation of blood cell production.

Animals↗
PubMed2003

Translational control of SCL-isoform expression in hematopoietic lineage choice.

We investigated the translational regulation of SCL protein expression and its role in hematopoietic lineage choice. We show that the expression of different SCL protein isoforms is regulated by signal transduction pathways that modulate translation initiation factor (eIF) function. A conserved small upstream open reading frame (uORF) in SCL transcripts acts as a cis-regulatory element for isoform expression. At the onset of erythroid differentiation, truncated SCL protein isoforms arise by alternative translation initiation and favor the erythroid lineage. In comparison, full-length SCL proteins are more efficient at enhancing the megakaryocyte lineage. Together, our studies unravel translational control as a novel mechanism regulating hematopoietic outcome.

Animals↗
PubMed2002

The SCL complex regulates c-kit expression in hematopoietic cells through functional interaction with Sp1.

The combinatorial interaction among transcription factors is believed to determine hematopoietic cell fate. Stem cell leukemia (SCL, also known as TAL1 [T-cell acute lymphoblastic leukemia 1]) is a tissue-specific basic helix-loop-helix (bHLH) factor that plays a central function in hematopoietic development; however, its target genes and molecular mode of action remain to be elucidated. Here we show that SCL and the c-Kit receptor are coexpressed in hematopoietic progenitors at the single-cell level and that SCL induces c-kit in chromatin, as ectopic SCL expression in transgenic mice sustains c-kit transcription in developing B lymphocytes, in which both genes are normally down-regulated. Through transient transfection assays and coimmunoprecipitation of endogenous proteins, we define the role of SCL as a nucleation factor for a multifactorial complex (SCL complex) that specifically enhances c-kit promoter activity without affecting the activity of myelomonocytic promoters. This complex, containing hematopoietic-specific (SCL, Lim-only 2 (LMO2), GATA-1/GATA-2) and ubiquitous (E2A, LIM- domain binding protein 1 [Ldb-1]) factors, is tethered to DNA via a specificity protein 1 (Sp1) motif, through direct interactions between elements of the SCL complex and the Sp1 zinc finger protein. Furthermore, we demonstrate by chromatin immunoprecipitation that SCL, E2A, and Sp1 specifically co-occupy the c-kit promoter in vivo. We therefore conclude that c-kit is a direct target of the SCL complex. Proper activation of the c-kit promoter depends on the combinatorial interaction of all members of the complex. Since SCL is down-regulated in maturing cells while its partners remain expressed, our observations suggest that loss of SCL inactivates the SCL complex, which may be an important event in the differentiation of pluripotent hematopoietic cells.

3T3 Cells↗
PubMed2002

Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist.

alpha(4)beta(1) and alpha(4)beta(7) integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. The effectiveness of anti-integrin antibodies to attenuate a number of inflammatory/immune conditions provides a strong rationale to target integrins for drug development. Important advances have been made in identifying potent and selective candidates, peptides and peptidomimetics, for further development. Herein, we report the discovery of a series of novel N-benzoyl-L-biphenylalanine derivatives that are potent inhibitors of alpha4 integrins. The potency of the initial lead compound (1: IC(50) alpha(4)beta(7)/alpha(4)beta(1)=5/33 microM) was optimized via sequential manipulation of substituents to generate low nM, orally bioavailable dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. The SAR also led to the identification of several subnanomolar antagonists (134, 142, and 143). Compound 81 (TR-14035; IC(50) alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM) has completed Phase I studies in Europe. The synthesis, SAR and biological evaluation of these compounds are described.

Cell Adhesion↗
PubMed2002

Health-related quality of life in early rheumatoid arthritis: impact of disease and treatment response.

OBJECTIVE: To document the burden of early rheumatoid arthritis (RA) on health-related quality of life (HQL) and compare changes in HQL across 2 treatments. STUDY DESIGN: Analysis of HQL scores among patients enrolled in a multicenter, double-blind, randomized control trial of early RA treatment. PATIENTS AND METHODS: A total of 424 patients with early RA were randomized to 1 of 2 treatment groups: etanercept or methotrexate. Patients were treated and followed for 52 weeks. Health-related quality of life was assessed before and throughout treatment using the Medical Outcomes Study Short Form 36 Health Survey (SF-36) and the Health Assessment Questionnaire (HAQ). The HQL burden of RA was established by comparing SF-36 scale scores to general US population norms. The impact of treatment on HQL was determined by comparing scores on both SF-36 and HAQ scales. RESULTS: Before treatment, RA patients showed significant decrements in scores on all SF-36 scales and summary measures in comparison with age- and sex-matched general US population norms, multivariate analysis of variance (MANOVA) F(8,2815) = 204.6, P < .0001. After 52 weeks of treatment, 7 of 8 SF-36 scales and the physical summary measure remained significantly below the general US population norm, MANOVA F(8,2815) = 41.9, P < .0001. Patients randomized to etanercept showed significantly better HQL improvement earlier in treatment than patients randomized to methotrexate on the SF-36 physical summary, MANOVA F(10,4230) = 6.1, P< .0001, the SF-36 arthritis-specific health index, MANOVA F(10,4230) = 8.5, P < .0001, and the HAQ, MANOVA F(10,4230) = 14.7, P < .0001. At 52 weeks, there were no significant differences between treatment groups. CONCLUSIONS: Rheumatoid arthritis places tremendous disease burden on patients' HQL. Successful treatment of early RA improved HQL. Etanercept showed a rapid HQL response.

Adult↗