Characterization and localization of human type10 17β‐hydroxysteroid dehydrogenase

He, Xue‐Ying; Merz, George; Yang, Yutao; Mehta, Penkaj; Schulz, Horst; Yang, Song‐Yu

doi:10.1046/j.0014-2956.2001.02421.2421.x

Cited by 66 publications

(68 citation statements)

References 54 publications

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“…HSD10(R130C) and HSD10(E249Q), possess the same Cterminal sequence as the WT HSD10, they can be detected by immunoblotting analysis with the R228 antiserum (21). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Protein concentrations were determined by use of the Micro BCA protein assay kit obtained from PIERCE according to the instructions of the manufacturer. Immunoblotting was performed as described (3,21) except that 10 micrograms of total cellular proteins were separated on a 10% SDS-polyacrylamide gel and then transferred to a nitrocellulose membrane. Protein bands were detected by use of the enhanced chemiluminescent substrate obtained from PIERCE (#32106) according to the instructions of the manufacturer.…”

Section: Tertiary Structural Model Of Hsd10(e249q)mentioning

confidence: 99%

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Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism

Yang¹,

He²,

Olpin

et al. 2009

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

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Mutations in the HSD17B10 gene were identified in two previously described mentally retarded males. A point mutation c.776G>C was found from a survivor (SV), whereas a potent mutation, c.419C>T, was identified in another deceased case (SF) with undetectable hydroxysteroid (17␤) dehydrogenase 10 (HSD10) activity. Protein levels of mutant HSD10(R130C) in patient SF and HSD10(E249Q) in patient SV were about half that of HSD10 in normal controls. The E249Q mutation appears to affect HSD10 subunit interactions, resulting in an allosteric regulatory enzyme. For catalyzing the oxidation of allopregnanolone by NAD ؉ the Hill coefficient of the mutant enzyme is Ϸ1.3. HSD10(E249Q) was unable to catalyze the dehydrogenation of 2-methyl-3-hydroxybutyryl-CoA and the oxidation of allopregnanolone, a positive modulator of the ␥-aminobutyric acid type A receptor, at low substrate concentrations. Neurosteroid homeostasis is critical for normal cognitive development, and there is increasing evidence that a blockade of isoleucine catabolism alone does not commonly cause developmental disabilities. The results support the theory that an imbalance in neurosteroid metabolism could be a major cause of the neurological handicap associated with hydroxysteroid (17␤) dehydrogenase 10 deficiency.developmental disabilities ͉ HSD10 deficiency ͉ hydroxyacyl-CoA dehydrogenase

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“…HSD10(R130C) and HSD10(E249Q), possess the same Cterminal sequence as the WT HSD10, they can be detected by immunoblotting analysis with the R228 antiserum (21). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Tertiary Structural Model Of Hsd10(e249q)mentioning

confidence: 99%

Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism

Yang¹,

He²,

Olpin

et al. 2009

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

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“…Enzymes of the SDR-containing protein family have been shown to catalytically interact with estrogens and androgens (Filling et al, 2002;Kallberg et al, 2002). For instance, 17-hydroxysteroid dehydrogenases (17-HSD) are important in regulating the biological potency of steroid hormones by catalysing oxidation or reduction at position 17 (Filling et al, 2001;He et al, 2001). However, these enzymes could not translocate to the nuclei in response to sex hormones.…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo

et al. 2004

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Human WWOX gene encodes a proapoptotic WW domaincontaining oxidoreductase WOX1 (also named WWOX, FOR2 or WWOXv1). Apoptotic and stress stimuli activate WOX1 via Tyr33 phosphorylation and nuclear translocation. WOX1 possesses a tetrad NSYK motif in the Cterminal short-chain alcohol dehydrogenase/reductase (SDR) domain, which may bind estrogen and androgen. Here, we determined that 17b-estradiol (E 2 ) activated WOX1, p53 and ERK in COS7 fibroblasts, primary lung epithelial cells, and androgen receptor (AR)-negative prostate DU145 cells, but not in estrogen receptor (ER)-positive breast MCF7 cells. Androgen also activated WOX1 in the AR-negative DU145 cells. These observations suggest that sex hormone-mediated Tyr33 phosphorylation and nuclear translocation of WOX1 is independent of ER and AR. Stress stimuli increase physical binding of p53 with WOX1 in vivo. We determined here that E 2 increased the formation of p53/WOX1 complex and their nuclear translocation in COS7 cells; however, nuclear translocation of this complex could not occur in MCF7 cells. By immunohistochemistry, we determined that progression of prostate from normal to hyperplasia, cancerous and metastatic stages positively correlate with upregulation and activation of WOX1 and WOX2 (FOR1/WWOXv2). In contrast, breast cancer development to a premetastatic state is associated with upregulation and Tyr33 phosphorylation of cytosolic WOX1 and WOX2, followed by significant downregulation or absent expression during metastasis. These Tyr33-phosphorylated proteins are mostly located in the mitochondria without translocating to the nuclei, which is comparable to those findings in cultured breast cancer cells. Together, sex steroid hormone-induced activation of WOX1 and WOX2 is independent of ER and AR, and this activation positively correlates with cancerous progression of prostate and breast to a premetastatic state.

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“…Using the yeast two-hybrid system, our group identified ABAD as a short-chain oxidoreductase which interacted with Aβ and is present in the mitochondrial matrix compartment (as well as other intracellular compartments, such as endoplasmic reticulum) [10,81]. ABAD is an enzyme involved in metabolic homeostasis, particularly in the context of isoleucine degradation [82][83][84][85]. The enzyme methyl-3-hydroxybutryryl-CoA dehydrogenase (MHBD), which catabolizes isoleucine and branched-chain fatty acids, is identical to ABAD.…”

Section: Targets Of Aβ In Mitochondriamentioning

confidence: 99%

“…ABAD shares many features with other members of the family of shortchain dehydrogenase reductases, including binding of an NAD/NADP cofactor and properties of the catalytic site. Its unique properties include participation in isoleucine degradation, presence in mitochondria (as well as, to a lesser extent, endoplasmic reticulum in certain cells), a broad range of substrates, and the ability to bind Aβ and to facilitate Aβ-induced cell stress [81][82][83][84][85][86][87][88][89].…”

Section: Targets Of Aβ In Mitochondriamentioning

confidence: 99%

Mitochondrial amyloid-beta peptide: Pathogenesis or late-phase development?

Yan

Xiong

Stern

2006

JAD

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Abstract. Mitochondrial and metabolic dysfunction have been linked to Alzheimer's disease for some time. Key questions regarding this association concern the nature and mechanisms of mitochondrial dysfunction, and whether such changes in metabolic properties are pathogenic or secondary, with respect to neuronal degeneration. In terms of mitochondria and Alzheimer's, altered function could reflect intrinsic properties of this organelle, potentially due to mutations in mitochondrial DNA, or extrinsic changes secondary to signal transduction mechanisms activated in the cytosol. This review presents data relevant to these questions, and considers the implication of recent findings demonstrating the presence of amyloid-β peptide in mitochondria, as well as intra-mitochondrial molecular targets with which it can interact. Regardless of the underlying mechanism(s), it is likely that mitochondrial dysfunction contributes to oxidant stress which is commonly observed in brains of patients with Alzheimer's and transgenic models of Alzheimer's-like pathology.

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Characterization and localization of human type10 17β‐hydroxysteroid dehydrogenase

Cited by 66 publications

References 54 publications

Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism

Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism

17β-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo

Mitochondrial amyloid-beta peptide: Pathogenesis or late-phase development?

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