The long-term objective of this proposal is a more complete understanding, at the molecular level, of the regulation of hemoglobin synthesis and the role of erythropoietin in this regulation. One aspect of the mechanism of erythropoietin action on red cell differentiation is that of initiation and control of transcription of the globin genes. The transformed mouse cell lines, IW32 and NNlO, which secrete erythropoietin constitutively, are good models in which to study this process since they can also be induced, by hemin or butyrate, to transcribe the alpha and beta globin loci. A control cell line (201), which does not secrete erythropoietin, transcribes the alpha globin message but not the beta after exposure to hemin or butyrate. The problem thus is one of the mechanism of differential gene expression and the possible role of trans-acting, inhibitory factors in the regulation of the beta globin gene. This model may be related to various human disorders in which either a globin gene is not expressed or one is expressed and should be suppressed to permit the expression of an alternative. IW32 cells have a rearranged and amplified erythropoietin gene and are being used to study the structural features that permit constitutive expression of the erythropoietin gene.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL030121-15
Application #
6109700
Study Section
Project Start
1998-06-01
Project End
2000-05-31
Budget Start
Budget End
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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He, B; Gross, M; Roizman, B (1998) The gamma134.5 protein of herpes simplex virus 1 has the structural and functional attributes of a protein phosphatase 1 regulatory subunit and is present in a high molecular weight complex with the enzyme in infected cells. J Biol Chem 273:20737-43
He, B; Gross, M; Roizman, B (1997) The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activa Proc Natl Acad Sci U S A 94:843-8
Picot, D; Loll, P J; Garavito, R M (1997) X-ray crystallographic study of the structure of prostaglandin H synthase. Adv Exp Med Biol 400A:107-11
Goldwasser, E (1996) Erythropoietin: a somewhat personal history. Perspect Biol Med 40:18-32

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