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At least 19 recordsLinked to original sources
PubMed1999

Yeast Sml1, a protein inhibitor of ribonucleotide reductase.

Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides; this step is rate-limiting in DNA precursor synthesis. A number of regulatory mechanisms ensure optimal deoxyribonucleotide pools, which are essential for cell viability. The best studied mechanisms are transcriptional regulation of the RNR genes during the cell cycle and in the response to DNA damage, and the allosteric regulation of ribonucleotide reductase by nucleoside triphosphates. Recently, another mode of RNR regulation has been hypothesized in yeast. A novel protein, Sml1, was shown to bind to the Rnr1 protein of the yeast ribonucleotide reductase; this interaction was proposed to inhibit ribonucleotide reductase activity when DNA synthesis is not required (Zhao, X., Muller, E.G.D., and Rothstein, R. (1998) Mol. Cell 2, 329-340). Here, we use highly purified recombinant proteins to directly demonstrate that the Sml1 protein is a strong inhibitor of yeast RNR. The Sml1p specifically binds to the yeast Rnr1p in a 1:1 ratio with a dissociation constant of 0.4 microM. Interestingly, Sml1p also specifically binds to the mouse ribonucleotide reductase R1 protein. However, the inhibition observed in an in vitro mouse ribonucleotide reductase assay is less pronounced than the inhibition in yeast and probably occurs via a different mechanism.

Animals↗
PubMed2000

Cellular adaptation to down-regulated iron transport into lymphoid leukaemic cells: effects on the expression of the gene for ribonucleotide reductase.

Ribonucleotide reductase is an iron-containing enzyme that is essential for DNA synthesis. Whereas previous studies have used various iron chelators to examine the relationship between cellular iron metabolism and ribonucleotide reductase activity in cells, they have not elucidated the relationship between iron transport into cells and the expression of the gene for ribonucleotide reductase. To investigate this, we examined ribonucleotide reductase mRNA, protein and enzyme activity in a novel line of CCRF-CEM cells (DFe-T cells) that display an approx. 60% decrease in their uptake of iron compared with the parental wild-type cell line. We found that DFe-T cells displayed an approx. 40% decrease in ribonucleotide reductase specific enzyme activity relative to wild-type cells without a change in their proliferation. Kinetic analysis of CDP reductase activity revealed an approx. 60% decrease in V(max) in DFe-T cells without a change in K(m). Despite the decrease in enzyme activity, the mRNA and protein for the R1 and R2 subunits of ribonucleotide reductase in DFe-T cells were similar to those of wild-type cells. ESR spectroscopy studies revealed that DFe-T cells had a 22% decrease in the tyrosyl free radical of the R2 subunit, suggesting that a larger amount of R2 protein was present as functionally inactive apo-R2 in these cells. Our studies indicate that ribonucleotide reductase activity in CCRF-CEM cells can be down-regulated by more than 50% in response to down-regulated iron transport without an adverse effect on cell proliferation. Furthermore, our studies suggest a regulatory link between ribonucleotide reductase activity and iron transport into these cells.

Adaptation, Physiological↗
PubMed2005

A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases.

Ribonucleotide reductase catalyzes the reduction of ribonucleotides to deoxyribonucleotides for DNA biosynthesis. A tyrosine residue in the small subunit of class I ribonucleotide reductase harbors a stable radical, which plays a central role in the catalysis process. We have discovered that an additional tyrosine residue, conserved in human small subunits hRRM2 and p53R2, is required for the radical formation and enzyme activity. Mutations of this newly identified tyrosine residue obliterated the stable radical and the enzymatic activity of human ribonucleotide reductases shown by electron paramagnetic resonance spectroscopy and enzyme activity assays. Three-dimensional structural analysis reveals for the first time that these two tyrosines are located at opposite sides of the diiron cluster. We conclude that both tyrosines are necessary in maintaining the diiron cluster of the enzymes, suggesting that the assembly of a dityrosyl-diiron radical cofactor center in human ribonucleotide reductases is essential for enzyme catalytic activity. These results should provide insights to design better ribonucleotide reductase inhibitors for cancer therapy.

Amino Acid Sequence↗
PubMed2004

Enhancement by effectors and substrate nucleotides of R1-R2 interactions in Escherichia coli class Ia ribonucleotide reductase.

Ribonucleotide reductases are a family of essential enzymes that catalyze the reduction of ribonucleotides to their corresponding deoxyribonucleotides and provide cells with precursors for DNA synthesis. The different classes of ribonucleotide reductase are distinguished based on quaternary structures and enzyme activation mechanisms, but the components harboring the active site region in each class are evolutionarily related. With a few exceptions, ribonucleotide reductases are allosterically regulated by nucleoside triphosphates (ATP and dNTPs). We have used the surface plasmon resonance technique to study how allosteric effects govern the strength of quaternary interactions in the class Ia ribonucleotide reductase from Escherichia coli, which like all class I enzymes has a tetrameric alpha(2) beta(2) structure. The component alpha(2)called R1 harbors the active site and two types of binding sites for allosteric effector nucleotides, whereas the beta(2) component called R2 harbors the tyrosyl radical necessary for catalysis. Our results show that only the known allosteric effector nucleotides, but not non-interacting nucleotides, promote a specific interaction between R1 and R2. Interestingly, the presence of substrate together with allosteric effector nucleotide strengthens the complex 2-3 times with a similar free energy change as the mutual allosteric effects of substrate and effector nucleotide binding to protein R1 in solution experiments. The dual allosteric effects of dATP as positive allosteric effector at low concentrations and as negative allosteric effector at high concentrations coincided with an almost 100-fold stronger R1-R2 interaction. Based on the experimental setup, we propose that the inhibition of enzyme activity in the E. coli class Ia enzyme occurs in a tight 1:1 complex of R1 and R2. Most intriguingly, we also discovered that thioredoxin, one of the physiological reductants of ribonucleotide reductases, enhances the R1-R2 interaction 4-fold.

Allosteric Regulation↗
PubMed1985

Drug action on ribonucleotide reductase.

Ribonucleotide reductase catalyzes the rate-limiting step in DNA synthesis. It represents a key metabolic site at which specific inhibitors have been directed as potential antitumor agents. Several different classes of ribonucleotide reductase inhibitors have been generated and studied. Because of the nature of the DNA polymerase reaction in which all four dNTPs are required, the initial velocity vs dNTP concentration curve gives sigmoidal rather than hyperbolic kinetics. As a result, a 50 per cent decrease in ribonucleotide reductase activity causes a decrease in DNA polymerase activity of 75 per cent or greater depending on the ratio of [dNTP] to its Km. This has been demonstrated with theoretical calculations, actual DNA polymerase determinations and precursor studies in intact tumor cells. The structural requirements for a compound to serve as a specific inhibitor of ribonucleotide reductase, either as the non-heme iron or effector-binding subunit, are stringent. Each protein subunit comprising the active enzyme can be specifically and independently inhibited. When combinations of agents, each directed at one of the subunits of ribonucleotide reductase, are used, strong synergistic inhibition of L1210 cell growth and synergistic cytotoxicity result.

Animals↗
PubMed1981

Evidence for genetically independent allosteric regulatory domains of the protein M1 subunit of mouse ribonucleotide reductase.

Ribonucleotide reductase is responsible for the reduction of the 2'-hydroxy moiety of all four ribonucleoside diphosphates to the corresponding deoxyribonucleotides. The overall activity of the enzyme is regulated by the allosteric effectors ATP (activator) and dATP (inhibitor), and the enzyme's substrate specificity is also controlled by nucleotide effectors. For instance, wild type ribonucleotide reductase from mouse T-lymphoma (S49) cells requires dGTP as a positive effector for ADP reduction. This effect of dGTP causes a reciprocal inhibition of CDP reduction. The dGuo-L mutant cell line, resistant to growth inhibition by exogenous deoxyguanosine, contains a nucleotide-binding subunit, protein M1, that conveys to its CDP reductase an insensitivity to dGTP (and dTTP) inhibition. The dGuo-L protein M1 also shows a decreased capacity to use ADP as a substrate, and therefore, the regulation of the substrate specificity is altered in the mutant protein M1. Another mutant cell line, dGuo-200-1, is resistant to deoxyadenosine and its ribonucleotide reductase is abnormally resistant to inhibition by dATP. The isolated mutant protein M1 from dGuo-200-1 cells has a CDP reductase activity which is stimulated by dATP, unlike the wild type enzyme which is inhibited by dATP. It appears that this mutant enzyme has lost the capacity to distinguish between dATP and ATP, but is still sensitive to regulation by dGTP and dTTP. Thus, the site of protein M1 regulating overall activity is altered in the dGuo-200-1 mutant, while the site regulating substrate specificity is normal. These characteristics of the mutants provide genetic evidence for two independent allosteric domains of protein M1, each responsible for a different aspect of nucleotide sensitivity of ribonucleotide reductase.

Adenosine Triphosphate↗
PubMed1982

Structure of the tyrosyl radical in bacteriophage T4-induced ribonucleotide reductase.

Ribonucleotide reductase induced by bacteriophage T4 in Escherichia coli contains an organic free radical necessary for enzymatic activity. Its EPR spectrum at 77K is similar to but not identical with that of the corresponding radical in the enzyme from uninfected E. coli studied previously. Isotope substitutions now show that the radical in the T4-induced enzyme also is localized to a tyrosine residue with its spin density delocalized over the aromatic ring of tyrosine. The difference between the radicals of the T4-induced and the E. coli ribonucleotide reductases, as reflected in the hyperfine patterns of their EPR spectra, is suggested to be due to slightly different radical geometries, resulting from a twist of about 10 degrees around the bond between the aromatic ring and the methylene group in the tyrosine radical. Hydroxyurea destroys the free radicals of both ribonucleotide reductases and also their catalytic activities. Both enzymes are considerably more sensitive to hydroxyurea during catalysis than in the noncatalytic state. However, when compared to the bacterial ribonucleotide reductase, the T4-induced enzyme shows an overall approximately 10 times higher sensitivity to hydroxyurea, judging from the drug concentrations needed to destroy the radicals and inhibit the activities. This result may reflect a difference in accessibility for the drug to the active sites of the enzymes.

Electron Spin Resonance Spectroscopy↗
PubMed1978

Allosteric regulation of calf thymus ribonucleotide reductase.

Ribonucleotide reductase was purified 3400-fold from calf thymus. The enzyme preparation was essentially free of kinases and phosphatases and therefore allowed a conclusive study of the allosteric regulation of a eukaryotic ribonucleotide reductase to be made for the first time. Comparable maximal activities were obtained for the reduction of all four ribonucleotide substrates in the presence of their optimal stimulatory effectors. These and other results strongly argue for the existence of only one ribonucleotide reductase in mammalian cells. No reduction was observed in the absence of effector. The reduction of CDP and UDP both required ATP, with no stimulatory effect of any other nucleoside triphosphate. The only activator of GDP reduction was dTTP and the only activator of ADP reduction was dGTP. Reduction of the purine ribonucleotides was further stimulated by ATP but only in combination with dTTP or dGTP. The reduction of all four ribonucleotides was strongly inhibited by dATP, the inhibition being partly released by ATP. The data can be integrated into a scheme which links ribonucleotide reduction to DNA synthesis.

Allosteric Regulation↗
PubMed1990

Two genes differentially regulated in the cell cycle and by DNA-damaging agents encode alternative regulatory subunits of ribonucleotide reductase.

Ribonucleotide reductase activity is essential for progression through the cell cycle, catalyzing the rate-limiting step for the production of deoxyribonucleotides needed for DNA synthesis. The enzymatic activity of the enzyme fluctuates in the cell cycle with an activity maximum in S phase. We have identified and characterized two Saccharomyces cerevisiae genes encoding the regulatory subunit of ribonucleotide reductase, RNR1 and RNR3. They share approximately 80% amino acid identity with each other and 60% with the mammalian homolog, M1. Genetic disruption reveals that the RNR1 gene is essential for mitotic viability, whereas the RNR3 gene is not essential. A high-copy-number clone of RNR3 is able to suppress the lethality of rnr1 mutations. Analysis of mRNA levels in cell-cycle-synchronized cultures reveals that the RNR1 mRNA is tightly cell-cycle regulated, fluctuating 15- to 30-fold, and is coordinately regulated with the POL1 mRNA, being expressed in the late G1 and S phases of the cell cycle. Progression from the alpha-factor-induced G1 block to induction of RNR1 mRNA is blocked by cycloheximide, further defining the requirement for protein synthesis in the G1- to S-phase transition. Both RNR1 and RNR3 transcripts are inducible by treatments that damage DNA, such as 4-nitroquinoline-1-oxide and methylmethanesulfonate, or block DNA replication, such as hydroxyurea. RNR1 is inducible 3- to 5-fold, and RNR3 is inducible greater than 100-fold. When MATa cells are arrested in G1 by alpha-factor, RNR1 and RNR3 mRNA is still inducible by DNA damage, indicating that the observed induction can occur outside of S phase. Inhibition of ribonucleotide reductase activity by hydroxyurea treatment results in arrest of the cell cycle in S phase as large budded, uninucleate cells. This specific cell-cycle arrest is independent of the RAD9 gene, defining a separate pathway for the coordination of DNA synthesis and cell-cycle progression.

Amino Acid Sequence↗
PubMed1996

Electron paramagnetic resonance and nuclear magnetic resonance studies of class I ribonucleotide reductase.

Ribonucleotide reductase catalyses the reduction of ribonucleotides to the corresponding deoxyribonucleotides needed for DNA synthesis. This review describes recent studies on the iron/tyrosyl free radical site in the R2 protein of iron-containing (class I) ribonucleotide reductases. The active enzyme is composed of two homodimeric proteins, R1 and R2. Active protein R2 contains a diiron-oxygen site and a neighboring free radical on a tyrosyl residue per polypeptide chain. The properties of the different redox states of the diiron center in protein R2 are discussed, as well as the formation of the iron/radical site and its possible involvement in long range electron transfer from the substrate binding site in protein R1. The EPR properties of oxidized neutral tyrosyl free radicals are described, and also of tryptophan free radicals found in studies of a mutant of the R2 protein, which lacks the tyrosyl radical site. NMR studies on protein R2 include observations of paramagnetically shifted resonances. Structural NMR studies have been performed on its highly mobile C-terminal domain as well as the corresponding oligopeptide which interacts with protein R1.

Animals↗
PubMed1985

Nucleoside 5'-triphosphate analogs as positive and negative effectors of mammalian ribonucleotide reductase.

Ribonucleotide reductase activity is strongly regulated by nucleoside 5'-triphosphates acting as positive and negative effectors. With the use of dGTP analogs, araGTP and dITP, it was found that the structural requirements of dGTP to serve as a positive effector of ADP reductase were not the same as the requirements for dGTP to serve as a negative effector of CDP and ADP reductase activities. The dTTP analogs methylenedTTP and dideoxyTTP also gave different responses in terms of activating GDP reductase activity and inhibiting CDP and ADP reductase activities. Etheno-ATP and etheno-dATP were inactive as positive and negative effectors, respectively, of CDP reductase activity. DideoxyATP was less active than dATP as a negative effector. Formycin ATP was a very poor substitute for ATP as a positive effector of CDP reductase. These studies indicate that the effector sites are very specific in terms of binding nucleoside triphosphates as positive or negative modulators of ribonucleotide reductase activity.

Animals↗
PubMed1989

Mechanisms of drug resistance to inhibitors directed at the individual subunits of ribonucleotide reductase.

Ribonucleotide reductase consists of two non-identical subunits, non-heme iron subunit (NHI) and effector-binding subunit (EB), that are encoded by different genes and that can be specifically and independently inhibited. L1210 cell lines were selected for resistance to hydroxyurea (HU-7), deoxyadenosine (Y-8), or the combination of pyrazoloimidazole and deoxyadenosine (ED2). The gene for the NHI was amplified in the HU-7, Y-8, and ED2 cell lines; there was no amplification of the gene for the EB. The mRNA for the NHI was increased in the HU-7, Y-8, and ED2 cells, but there was no change in the mRNA levels for the EB. Reductase activity was increased in the HU-7, ED2 cells, but not in the Y-8 cells. The reductase activities in the Y-8 and the ED2 cells were not subject to feedback inhibition by dATP. These data show that the mechanisms of resistance to inhibitors directed at this reductase are varied and do not require increased enzyme activity. Further, gene amplification or increased mRNA levels did not necessarily result in increased levels of cellular enzyme.

Animals↗
PubMed2006

A Ferrous-Triapine complex mediates formation of reactive oxygen species that inactivate human ribonucleotide reductase.

Ribonucleotide reductase plays a central role in cell proliferation by supplying deoxyribonucleotide precursors for DNA synthesis and repair. The holoenzyme is a protein tetramer that features two large (hRRM1) and two small (hRRM2 or p53R2) subunits. The small subunit contains a di-iron cluster/tyrosyl radical cofactor that is essential for enzyme activity. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP) is a new, potent ribonucleotide reductase inhibitor currently in phase II clinical trials for cancer chemotherapy. Ferric chloride readily reacts with Triapine to form an Fe(III)-(3-AP) complex, which is reduced to Fe(II)-(3-AP) by DTT. Spin-trapping experiments with 5,5-dimethyl-1-pyrroline-N-oxide prove that Fe(II)-(3-AP) reduces O2 to give oxygen reactive species (ROS). In vitro activity assays show that Fe(II)-(3-AP) is a much more potent inhibitor of hRRM2/hRRM1 and p53R2/hRRM1 than Triapine. Electron paramagnetic resonance measurements on frozen solutions of hRRM2 and p53R2 show that their tyrosyl radicals are completely quenched by incubation with Fe(II)-(3-AP). However, the enzyme activity is maintained in protein samples supplemented with catalase alone or in combination with superoxide dismutase. Furthermore, catalase alone or in combination with superoxide dismutase markedly decreases the antiproliferative effect of Triapine in cytotoxicity assays. These results indicate that Triapine-induced inhibition of ribonucleotide reductase is caused by ROS. We suggest that ROS may ultimately be responsible for the pharmacologic effects of Triapine in vivo.

Cell Line, Tumor↗
PubMed1992

cDNA sequence of the small subunit of the hamster ribonucleotide reductase.

Ribonucleotide reductase activity is markedly elevated in cell lines selected for resistance to hydroxyurea, a cytotoxic drug known specifically to inhibit ribonucleotide reductase. From a cDNA library constructed from a highly hydroxyurea-resistant hamster lung cell line, 600H in which the activity is elevated more than 80-fold, we have isolated a full length cDNA for the small subunit of the reductase. The cDNA is 3.48 kb long with an open reading frame of 1158 nucleotides and a long 3' flanking region of 2169 nucleotides from the termination codon. The derived polypeptide sequence is closely similar to the small subunit of the mouse, differing from it in 20 amino acid positions. Most of these replacements occur in the N-terminal segment of the protein. The hamster subunit does not contain 4 amino acid residues found in the mouse small subunit near the C-terminal end. RNA blots probed with the cDNA show two poly(A)+ RNA species which are elevated in hydroxyurea-resistant cells.

Amino Acid Sequence↗
PubMed1992

Factors affecting the mRNA levels for the non-heme iron and effector-binding subunits of ribonucleotide reductase.

Ribonucleotide reductase which catalyzes the rate-limiting step in the de novo synthesis of dNTPs is composed of two non-identical protein subunits which are not under coordinate control in terms of synthesis and degradation. The mRNAs for the effector-binding (EB) and non-heme iron (NHI) subunits are likewise not under coordinate control during cell cycle traverse. Inhibitors directed at the specific subunits of ribonucleotide reductase block DNA synthesis. These current studies show that drugs such as IMPY or hydroxyurea which specifically inhibit the NHI subunit cause a marked increase in the steady-state level of the mRNA for the NHI subunit while resulting in a decrease in the level of mRNA for the EB subunit. In cells treated with deoxyadenosine, the patterns of the mRNAs for the NHI and EB subunits were different from those seen in the IMPY- or hydroxyurea-treated cells. Control experiments utilizing inhibitors (aphidicolin or araC) directed at DNA polymerase showed that the pattern of changes in the mRNA levels for the NHI and EB subunits were specific for the reductase inhibitors. These changes in the mRNAs for the NHI and EB subunits may be due to drug-induced alterations in transcription rates and/or degradation rates for the specific mRNAs.

Animals↗
PubMed1988

Molecular and cellular characterization of drug resistant hamster cell lines with alterations in ribonucleotide reductase.

Ribonucleotide reductase consists of 2 protein components frequently called M1 and M2. Hydroxyurea specifically inhibits DNA synthesis by interacting with the M2 protein and destroying a unique tyrosyl-free radical. We have carried out a molecular and cellular characterization of 2 Chinese hamster ovary cell lines exhibiting either low (HN(R)-AT) or relatively high (H(R)-R2T) resistance to the cytotoxic effects of hydroxyurea. Both drug-resistant lines have an increased level of ribonucleotide reductase activity. EPR measurements for tyrosyl-free radical content and studies with M1-specific antibodies indicated that the elevation in enzyme activity was entirely due to an increase in the M2 component. Studies with M1 cDNA showed that both drug-resistant cell lines contained a wild-type level of M1 mRNA and a wild-type M1 gene copy number. Studies with M2 cDNA indicated that the 2 drug-resistant lines possessed elevated levels of M2 message that could explain the observed increase in M2 component. The elevation of M2 mRNA in the most resistant line, H(R)-R2T, was due to an increase in M2 gene copy number. The low resistant cell line, HN(R)-AT, exhibited a wild-type M2 gene copy number, indicating that the increase in M2 gene message occurred through a process other than gene amplification. Enzyme kinetic studies with partially purified preparations from both drug resistant lines showed reduced sensitivity to hydroxyurea and to the negative allosteric effector, dATP. In addition to hydroxyurea, H(R)-R2T cells were also resistant to several other drugs whose site of action is the M2 component. Furthermore, H(R)-R2T cells were not cross-resistant to colchicine or puromycin, suggesting that hydroxyurea-resistant cells do not share the multi-drug resistance phenotype, which is frequently associated with cross-resistance to these drugs.

Animals↗
PubMed1986

Production and characterization of monoclonal antibodies against the two subunits proteins B1 and B2 of Escherichia coli ribonucleotide reductase.

Ribonucleotide reductase from Escherichia coli consists of two nonidentical subunits, named protein B1 (170 000) and protein B2 (87 000). We purified and characterized five monoclonal antibodies against B1 and three against B2 from hybridomas obtained by fusion of spleen cells from immunized mice and the myeloma cell line P3-X63Ag8. All are of the IgG1 class with a high affinity for the antigen with dissociation constants in the nanomolar range. Four of the anti-B1 monoclonals and all three anti-B2 monoclonals neutralize reductase activity while one anti-B1 monoclonal binds tightly to B1 without affecting its activity. Fab fragments prepared from three anti-B1 monoclonals had similar dissociation constants. The anti-B1 monoclonals interacted with separate epitopes while two of the anti-B2 monoclonals appeared to react with the same epitope. In the case of B1, various allosteric states of the protein induced by binding of effectors had no apparent effect on the interaction with monoclonals, nor did their binding prevent subsequent binding of effectors. With B2, binding of monoclonals did not affect the typical electron paramagnetic resonance spectrum of the protein and thus did not involve either the tyrosyl free radical or the iron center of B2. All neutralizing antibodies interfered with the interaction between the two subunits, explaining their effect on enzyme activity, since active ribonucleotide reductase consists of a B1-B2 complex.

Animals↗
PubMed1989

Changes in the distribution of insulin-like growth factor I, thioredoxin, thioredoxin reductase and ribonucleotide reductase during the development of the retina.

The postnatal development of the rat retina offers good opportunities to follow migration and differentiation of neuroectodermal cells. In this study we have analyzed, by immunohistochemical methods, the distribution of several protein antigens and the trophic peptide insulin-like growth factor I (IGF-I; somatomedin-C). The latter contains disulfide bonds, which in vitro are reduced by the thioredoxin system, i.e. thioredoxin, thioredoxin reductase and NADPH. Ribonucleotide reductase provides growing cells with deoxyribonucleotides, necessary for DNA synthesis, and thioredoxin is an in vitro hydrogen donor. By immunofluorescence IGF-I immunoreactivity was observed throughout the Müller neuroglial cells in the developing retina, but only to a very small extent in the mature retina. Nerve cells showed transient expression of IGF-I during their development. The IGF-I immunoreactivity is likely to be due to local synthesis, since we could demonstrate retinal IGF-I mRNA. Treatment with the transport-blocking agent colchicine caused the Müller glial cells and the retinal pigment epithelium cells to become IGF-I immunoreactive. Thioredoxin and thioredoxin reductase immunoreactivities are confined to neurons and photoreceptor cells in the developing retina. Ribonucleotide reductase subunit M1 immunoreactivity was only observed during the first postnatal week in proliferating neuroectodermal cells. In conclusion, IGF-I and ribonucleotide reductase subunit M1 immunoreactivities are transiently expressed by neuroectodermal cells in the developing rat retina. In contrast, the proteins of the thioredoxin system are demonstrable also in the mature retina.

Animals↗