The human globin genes provide a very useful model for the study of the factors involved in regulation of gene expression. Studies of mutant beta-thalassemia genes have ellucidated numerous mechanisms by which mutations can decrease or abolish gene expression in eukaryotic cells. Studies of delta beta-thalassemia and hereditary persistence of fetal hemoglobin on the other hand, have ellucidated mechanisms by which promoter mutations may lead to increased expression of the involved genes. However, the most difficult question which remains unanswered relates to the study of the factors involved in the developmental switch from fetal to adult globin production. We will attempt to shed some light on this phenomenon by studying a very unique human disorder where both fetal globin genes (G gamma and A gamma) are over-expressed in adult life in the absence of a major deletion in the beat-globin gene cluster. We have already characterized the phenotype of this condition in detail and described a promoter mutation in the beta- globin gene on the delta beta-thalassemia chromosome. We propose to search for the mutation(s) responsible for the failure of the switch from fetal to adult globin production on the involved chromosome. Another important aspect of gene regulation is the interaction of the different gene promoters and enhancers which results in tissue- specific and stage-specific gene expression. We have identified important differences in the enhancer requirement of the alpha- and beta-globin gene promoters. We propose to search for an endogenous enhancer in the alpha-globin gene and test its tissue-specificity in relevant cell lines. Hopefully, the insights obtained from such studies which utilize experiments of nature (delta beta- thalassemia) and experiments utilizing in vitro manipulations of human genes will serve to advance our understanding of the process of gene regulation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Suny Downstate Medical Center
Schools of Medicine
United States
Zip Code
Ren, S; Wong, B Y; Li, J et al. (1996) Production of genetically stable high-titer retroviral vectors that carry a human gamma-globin gene under the control of the alpha-globin locus control region. Blood 87:2518-24
Ren, S; Li, J; Atweh, G F (1996) CACCC and GATA-1 sequences make the constitutively expressed alpha-globin gene erythroid-responsive in mouse erythroleukemia cells. Nucleic Acids Res 24:342-7
Cowley Jr, A W; Roman, R J (1996) The role of the kidney in hypertension. JAMA 275:1581-9
Jeha, S; Luo, X N; Beran, M et al. (1996) Antisense RNA inhibition of phosphoprotein p18 expression abrogates the transformed phenotype of leukemic cells. Cancer Res 56:1445-50
Luo, X N; Reddy, J C; Yeyati, P L et al. (1995) The tumor suppressor gene WT1 inhibits ras-mediated transformation. Oncogene 11:743-50
Luo, X N; Mookerjee, B; Ferrari, A et al. (1994) Regulation of phosphoprotein p18 in leukemic cells. Cell cycle regulated phosphorylation by p34cdc2 kinase. J Biol Chem 269:10312-8
Ren, S; Luo, X N; Atweh, G F (1993) The major regulatory element upstream of the alpha-globin gene has classical and inducible enhancer activity. Blood 81:1058-66
Mookerjee, B; Arcasoy, M O; Atweh, G F (1992) Spontaneous delta- to beta-globin switching in K562 human leukemia cells. Blood 79:820-5
Brickner, H E; Zhu, X X; Atweh, G F (1991) A novel regulatory element of the human alpha-globin gene responsible for its constitutive expression. J Biol Chem 266:15363-8
Luo, X N; Arcasoy, M O; Brickner, H E et al. (1991) Regulated expression of p18, a major phosphoprotein of leukemic cells. J Biol Chem 266:21004-10

Showing the most recent 10 out of 11 publications