The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

Esther, Charles R.; Marino, Elaine M.; Howard, Tom E.; Machaud, Annie; Corvol, Pierre; Capecchi, Mario R.; Bernstein, Kenneth E.

doi:10.1172/jci119419

Cited by 266 publications

(228 citation statements)

References 28 publications

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“…On the other hand, the absence of Tp1 and Tp2 proteins in the null mice excludes the possibility that the spermiogenesis arrest was induced by premature translation. Male mice lacking individual Tp1, Tp2, or ACE showed either no effect or reduced fertility with normal sperm parameters (22)(23)(24). However, the fact that Tp1 and Tp2 double-knockout mice were infertile (25) further points to GRTH as a important regulator of spermiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is essential for spermatid development and completion of spermatogenesis

Tsai‐Morris

Lee

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

151

175

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Gonadotropin-regulated testicular RNA helicase (GRTH͞Ddx25), a member of the DEAD-box protein family, is a testis-specific gonadotropin-regulated RNA helicase that is present in Leydig cells and germ cells (meiotic spermatocytes and spermatids). In this study, we observed that GRTH is present in the nucleus, cytoplasm and chromatoid body of germ cells, and is an integral component of messenger ribonuclear protein particles. Male mice with a null mutation in the GRTH gene displayed normal gonadotropin and androgen profiles. However, they were sterile, with azoospermia caused by a complete arrest of spermiogenesis at step 8 of round spermatids and failure to elongate. Round spermatids of the null mice showed marked diminution in the size of chromatoid bodies. The transcription of relevant messages was not altered, but their translation was abrogated in a selective manner. Protein expression of transition proteins 1 and 2 and angiotensin-converting enzyme was completely absent, whereas that of the transcriptional activator cAMP responsive element modulator was intact. These findings indicate that GRTH participates in translational-associated events during germ cell development. Although significant apoptosis was present at the metaphase of meiosis in the GRTH-null mice, spermatogenesis proceeded to step 8 of spermiogenesis when complete arrest occurred. This progression may relate to compensatory gene function(s) and͞or the observed up-regulation of DNA repair proteins Rad51 and Dmc1. This study (i) demonstrates that GRTH is essential for completion of spermatogenesis, (ii) provides insights into intrinsic requirements for spermiogenesis, and (iii) establishes a model for studies of male infertility and contraception.messenger ribonuclear protein particle ͉ translation ͉ testis ͉ spermiogenesis ͉ sterility S permatogenesis is a complex process that depends on the integrated expression of an array of genes that must operate in a precise temporal sequence to produce normal mature spermatozoa (1, 2). Gene expression in haploid spermatids requires temporal uncoupling of transcription and translation. Two-thirds of the mRNAs in the adult mammalian testes are associated with specific proteins to form messenger ribonuclear protein (mRNP) particles and stored in the cytoplasm of spermatids (3). Translational activation of stored mRNAs at specific times is essential for the completion of spermatogenesis. Modulation of RNA structure by members of the DEAD-box family of RNA helicases is a crucial step in many different fundamental biological processes (4,5). This class of proteins participates in various aspects of RNA metabolism and translational events. However, little is known about the involvement of DEAD-box proteins in testicular germ cell development.Gonadotropin-regulated testicular RNA helicase (GRTH͞ Ddx25), a member of the DEAD-box protein family of RNA helicases, was cloned and characterized in our laboratory (6-8). This enzyme, which only shares 30-40% similarity with other helicases, including those predominantl...

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Section: Discussionmentioning

confidence: 99%

Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is essential for spermatid development and completion of spermatogenesis

Tsai‐Morris

Lee

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

151

175

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“…Our findings contrast with those of Siffert et al 10 but is consistent with other reports about this particular polymorphism. Although circumstantial evidence suggests that ACE plays an important role in the regulation of BP, particularly in the experimental setup of gene target in mice, animals that express only serum ACE but lack tissue ACE and have a low BP, 20 the relationship between ACE I/D polymorphism and hypertension is under controversy. Various reports described the D allele as a risk factor for EH in various populations whereas other studies disagree with that hypothesis.…”

Section: Discussionmentioning

confidence: 99%

GNB3 gene C825T and ACE gene I/D polymorphisms in essential hypertension in a Kazakh genetic isolate

Wang

Lin

et al. 2004

J Hum Hypertens

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The Kazakh inhabitants living in Barkol pasture of northeast China belong to a genetic isolate characterized by ethnically homogeneous and a communal pastoral lifestyle. To investigate whether the polymorphisms in the G-protein b-3 subunit (GNB3) gene and angiotensin-converting enzyme (ACE) gene are associated with essential hypertension (EH), we carried out a case-control study of 290 hypertensive subjects and 244 normotensive (NT) controls randomly selected from Kazakh populations of Barkol. A previous medical history of diabetes and hypertension, and body mass index (BMI) was recorded. Plasma glucose, triglyceride, and cholesterol were measured. The insertion/deletion (I/D) polymorphism of the ACE gene and the C825T polymorphism of the GNB3 gene were determined by the polymerase chain reaction (PCR) technique. The distributions of genotypes and alleles for the two polymorphisms did not differ significantly between the case and control populations, and odds ratio of EH related to the ACE gene D allele and GNB3 gene T allele was not significantly different from 1.0. Logistic regression analysis shows the variation at the GNB3 and ACE did not have any statistically significant synergistic effect on blood pressure (BP). Stratification of NT and untreated hypertensives according to I/D polymorphism of ACE gene and C825T polymorphism of GNB3 gene disclosed no significant difference across genotypes with respect to BMI, glucose, triglyceride, cholesterol, systolic and diastolic BP. In conclusion, the polymorphisms in the GNB3 gene and ACE gene, solely or combined, did not confer a significantly increased risk for the development of EH in the Kazakh isolate of northeast China.

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“…Although readily detected in i o, the functions of soluble ACE are unknown. Most or all of the established physiological functions of ACE can be ascribed to the membrane-anchored form [1,18]. However, shedding of ACE is likely to be tightly regulated, as has been shown for other shed membrane proteins, such as TNF-α, L-selectin and the amyloid precursor protein [19].…”

Section: Introductionmentioning

confidence: 97%

“…However, the reported somatic ACE cleavage site [22] is not consistent with data indicating that the size of the residual anchoring domain is 6.9 kDa [15], or that deletion of 47 residues proximal to the TM domain in testis ACE renders it catalytically inactive [21]. Testis ACE is identical with the C-terminal half of somatic ACE, which contributes 80-90 % of the catalytic activity of the somatic enzyme [18,27].…”

Section: Introductionmentioning

confidence: 98%

Shedding of somatic angiotensin-converting enzyme (ACE) is inefficient compared with testis ACE despite cleavage at identical stalk sites

Woodman

Oppong

Cook

et al. 2000

Biochemical Journal

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The somatic and testis isoforms of angiotensin-converting enzyme (ACE) are both C-terminally anchored ectoproteins that are shed by an unidentified secretase. Although testis and somatic ACE both share the same stalk and membrane domains the latter was reported to be shed inefficiently compared with testis ACE, and this was ascribed to cleavage at an alternative site [Beldent, Michaud, Bonnefoy, Chauvet and Corvol (1995) J. Biol. Chem. 270, 28962-28969]. These differences constitute a useful model system of the regulation and substrate preferences of the ACE secretase, and hence we investigated this further. In transfected Chinese hamster ovary cells, human somatic ACE (hsACE) was indeed shed less efficiently than human testis ACE, and shedding of somatic ACE responded poorly to phorbol ester activation. However, using several analytical techniques, we found no evidence that the somatic ACE cleavage site differed from that characterized in testis ACE. First, anti-peptide antibodies raised to specific sequences on either side of the reported cleavage site (Arg""$(\Leu""$)) clearly recognized soluble porcine somatic

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The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

Cited by 266 publications

References 28 publications

Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is essential for spermatid development and completion of spermatogenesis

Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is essential for spermatid development and completion of spermatogenesis

GNB3 gene C825T and ACE gene I/D polymorphisms in essential hypertension in a Kazakh genetic isolate

Shedding of somatic angiotensin-converting enzyme (ACE) is inefficient compared with testis ACE despite cleavage at identical stalk sites

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