The Histidine Triad Protein Hint Is Not Required for Murine Development or Cdk7 Function

Korsisaari, Nina; Rossi, Derrick J.; Luukko, Keijo; Huebner, Kay; Henkemeyer, Mark; Mäkelä, Tomi P.

doi:10.1128/mcb.23.11.3929-3935.2003

Cited by 28 publications

(24 citation statements)

References 30 publications

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“…This indicates that the tumor-suppressive effects of Hint1 are not confined to susceptibility to chemical carcinogenesis. Other investigators did not find an increase in spontaneous tumor in Hint1 À/À mice (Korsisaari et al, 2003). This may be because they followed the mice for only 18 months, the number of mice included in their study was not sufficient, and/or their mice have a different genetic background.…”

Section: Discussionmentioning

confidence: 96%

Hint1 is a haplo-insufficient tumor suppressor in mice

et al. 2005

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The HINT1 protein, a member of the histidine triad (HIT) family, is highly conserved in diverse species and ubiquitously expressed in mammalian tissues. However, its precise function in mammalian cells is not known. As a result of its structural similarity to the tumor-suppressor protein FHIT, we used homozygous-deleted Hint1 mice to study its role in tumorigenesis. We discovered that after 2 to 3 years of age the spontaneous tumor incidence in Hint1 À/À mice was significantly greater than that in wildtype Hint1 þ / þ mice (Po0.05). Using a well-established mouse model of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis we found a marked and significant (Po0.05) increase in the incidence of mammary and ovarian tumors in both, Hint1 À/À and þ /À mice versus þ / þ mice. The Hint1 À/À and þ /À mice had similar tumor incidence and similar tumor histologies. Therefore, deletion of Hint1 in mice enhances both spontaneous tumor development and susceptibility to tumor induction by DMBA. In addition, since the Hint1 þ /À tumors retained expression of the unmutated wildtype allele, Hint1 is haplo-insufficient with respect to tumor suppression in this model system.

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Section: Discussionmentioning

confidence: 96%

Hint1 is a haplo-insufficient tumor suppressor in mice

et al. 2005

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“…An interaction between human Hint1 and Cdk7 was observed in a yeast-two hybrid assay (38). However, studies with transgenic mice, in which the hint1 gene was deleted, failed to reveal a phenotype consistent with the regulation of Cdk7 (7). On the other hand, evidence from S. cerevisiae indicates that Hnt1 functions as a positive regulator of the Cdk7-homologous Kin28 kinase (3).…”

Section: Nucleoside and Leaving Group Specificity Of Bacterial Andmentioning

confidence: 99%

31P NMR and Genetic Analysis Establish hinT as the Only Escherchia coli Purine Nucleoside Phosphoramidase and as Essential for Growth under High Salt Conditions

Chou

Bieganowski

Shilinski

et al. 2005

Journal of Biological Chemistry

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Eukaryotic cells encode AMP-lysine (AMP-N-⑀-(N-␣acetyl lysine methyl ester) 5-phosphoramidate) hydrolases related to the rabbit histidine triad nucleotidebinding protein 1 (Hint1) sequence. Bacterial and archaeal cells have Hint homologs annotated in a variety of ways, but the enzymes have not been characterized, nor have phenotypes been described due to loss of enzymatic activity. We developed a quantitative 31 P NMR assay to determine whether Escherichia coli possesses an adenosine phosphoramidase activity. Indeed, soluble lysates prepared from wild-type laboratory E. coli exhibited activity on the model substrate adenosine 5-monophosphoramidate (AMP-NH 2 ). The E. coli Hint homolog, which had been comprehensively designated ycfF and is here named hinT, was cloned, overexpressed, purified, and characterized with respect to purine nucleoside phosphoramidate substrates. Bacterial hinT was several times more active than human or rabbit Hint1 on five model substrates. In addition, bacterial and mammalian enzymes preferred guanosine versus adenosine phosphoramidates as substrates. Analysis of the lysates from a constructed hinT knock-out strain of E. coli demonstrated that all of the cellular purine nucleoside phosphoramidase activity is due to hinT. Physiological analysis of this mutant revealed that the loss of hinT results in failure to grow in media containing 0.75 M KCl, 0.9 M NaCl, 0.5 M NaOAc, or 10 mM MnCl 2 . Thus, cation-resistant bacterial cell growth may be dependent on the hydrolysis of adenylylated and/or guanylylated phosphoramidate substrates by hinT.

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“…HINT1 appears to be structurally conserved from yeast through mammals suggesting a highly conserved function. However, no grossly observable deficiencies were noted in hint Ϫ/Ϫ mice, suggesting that other redundant genes can functionally compensate (20). HINT enzyme homologues hydrolyze adenosine-5Ј-monophosphoramidate (AMPNH 2 ) to AMP plus the leaving NH 2 group (19,21).…”

Section: Hint1mentioning

confidence: 99%

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

et al. 2004

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Microarray expression studies have reported decreased mRNA expression of histidine triad nucleotide-binding protein (HINT1) and cytosolic malate dehydrogenase (MDH1) in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Microarray results for neuroserpin (SERPINI1) mRNA in the DLPFC have reported increased and decreased expression in individuals with schizophrenia. The relative abundances of HINT1, MDH1, and SERPINI1 mRNA in the DLPFC in individuals with schizophrenia and controls were measured by real-time quantitative polymerase chain reaction (Q-PCR) and for HINT1 expression by in situ hybridization. The Q-PCR results were compared by analysis of covariance between individuals with schizophrenia and controls. Gene expression levels for HINT1, MDH1, and SERPINI1 were significantly different between the groups. The male individuals with schizophrenia compared to male controls showed reductions by 2.8-to 3.7-fold of HINT1, neuroserpin, and MDH1 by Q-PCR. The decreases in mRNA abundance for MDH1 (P ϭ 0.006), HINT1 (P ϭ 0.050), and neuroserpin (P ϭ 0.005) in DLPFC of male individuals with schizophrenia is consistent with prior reports. HINT1 mRNA was reduced significantly by 34% in layer VI. Though there were no significant interactions with gender, gene expression between female patients and the female control group did not differ. These results confirm earlier reports and suggest abnormalities of specific genes related to metabolic and protease activities in the DLPFC might be considered as part of a molecular pathway in male patients with schizophrenia.

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The Histidine Triad Protein Hint Is Not Required for Murine Development or Cdk7 Function

Cited by 28 publications

References 30 publications

Hint1 is a haplo-insufficient tumor suppressor in mice

Hint1 is a haplo-insufficient tumor suppressor in mice

31P NMR and Genetic Analysis Establish hinT as the Only Escherchia coli Purine Nucleoside Phosphoramidase and as Essential for Growth under High Salt Conditions

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

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