Regulation of the Human Inosine Monophosphate Dehydrogenase Type I Gene

Abstract

Catalysis of guanine nucleotide formation from IMP in the de novo purine synthetic pathway is carried out by two isoforms of the enzyme inosine monophosphate dehydrogenase (IMPDH) that are catalytically indistinguishable but are encoded by separate genes. In order to assess the potential for cell type-specific expression of IMPDH activity, we have characterized the IMPDH type I gene and identified three major RNA transcripts that are differentially expressed from three different promoters. A 4.0-kilobase pair (kb) mRNA containing 1.3 kb of 5-untranslated region is expressed in activated peripheral blood lymphocytes and to a far lesser extent in cultured tumor cell lines. The P1 promoter that regulates the transcription of this mRNA has a high degree of sequence identity to an Alu repetitive sequence. A transcript of 2.7 kb is found in a subset of the tumor cell lines examined, whereas a 2.5-kb mRNA species is universally expressed and is the prevalent mRNA in most cell lines and tissues. The relative strengths of the three promoter regions and the effects of variable extents of 5-flanking sequence on the P3 promoter differ in Jurkat T, as compared with Raji B lymphoid cell lines, demonstrating a complex cell type-specific transcriptional regulation of IMPDH type I gene expression.Inosine 5Ј-monophosphate dehydrogenase (IMPDH; 1 EC 1.1.1.205) is an essential, rate-limiting enzyme in the de novo guanine nucleotide synthetic pathway. It catalyzes the conversion of IMP to XMP at the purine metabolic branch point and provides sufficient guanine nucleotides for important cellular processes. The observations that the activity of IMPDH is tightly linked with both cellular proliferation and transformation (1-3) have led to an interest in developing IMPDH inhibitors for clinical use. Inhibition of IMPDH activity is associated with depletion of intracellular guanine nucleotide pools and has been shown both to inhibit cellular proliferation (4, 5) and to induce cell differentiation (6 -9). The specific reversibility by exogenous guanine of the biologic effects of IMPDH inhibitors on cell division and differentiation is a unique feature of such compounds that differentiates them from other inducers of cellular differentiation. IMPDH inhibitors have also been demonstrated to have considerable efficacy as immunosuppressive agents (10, 11) and prevent both B and T lymphocyte activation (12, 13).Human IMPDH activity is composed of the activities of two separate but very closely related IMPDH isoenzymes, termed type I and type II, that are encoded by separate genes located on chromosomes 7 and 3, respectively (14, 15). The corresponding cDNAs have been isolated (16, 17) and encode two distinct protein subunits of 56 kDa with 84% sequence identity. The two IMPDH proteins are tetrameric and are indistinguishable in their catalytic activities, substrate affinities, and K i values for known inhibitors (18 -20).The increased IMPDH activity observed in replicating or neoplastic cells is largely due to increased expression of the type I...

Phenotypic Characterization of a Large Family With RP10 Autosomal-Dominant Retinitis Pigmentosa: An Asp226Asn Mutation in the IMPDH1 Gene

“…11 Despite the role in nucleotide metabolism, it appears that mutant IMPDH1 only causes disease in the retina, where it is preferentially and strongly expressed within photoreceptor cells. 11,12 It remains to be determined whether mutant IMPDH1 causes adRP by interfering with nucleotide metabolism in photoreceptors.All disease-causing mutations identified in the IMPDH1 gene to date are missense mutations. Functional consequences of specific mutations are not well characterized.…”

“…IMPDH1 is expressed at high levels in kidney, pancreas, colon, peripheral blood leukocytes, fetal heart, brain, and retina. 11 Despite the role in nucleotide metabolism, it appears that mutant IMPDH1 only causes disease in the retina, where it is preferentially and strongly expressed within photoreceptor cells. 11,12 It remains to be determined whether mutant IMPDH1 causes adRP by interfering with nucleotide metabolism in photoreceptors.…”

Biased Distribution of Inverted and Direct Alus in the Human Genome: Implications for Insertion, Exclusion, and Genome Stability

“…Besides becoming a structural genetic component by integrating into an exon (Mullersman and Pfeffer 1995), Alu elements can serve in a regulatory capacity through diverse mechanisms. They also can behave as a modulator of DNA replication (Tsuchiya et al 1998), a positive ( Norris et al 1995;Gu et al 1997) or negative enhancer, a regulator of an enhancer, a mediator of alternative splicing, or have a role in genetic imprinting. Recently, Alus also have been proposed to downregulate translation in response to cellular stress and viral infection by antagonizing double-stranded RNA-activated kinase PKR activation (Chu et al 1998) and they are the subject of p53 transcriptional control (Chesnokov et al 1996).…”

On the Role of IMPDH1 in Retinal Degeneration

“…Three different promoters have been identified in the human type 1 form of the protein which give rise to three distinct transcripts. This may be an indication that IMPDH1 expression is regulated in a complex cell type-specific manner (Gu et al, 1997). Investigations into the expression patterns of IMPDH1, IMPDH2 and HPRT within the retina have not been previously undertaken.…”