Genomic organization of mouse ZAKI-4 gene that encodes ZAKI-4 alpha and beta isoforms, endogenous calcineurin inhibitors, and changes in the expression of these isoforms by thyroid hormone in adult mouse brain and heart

Mizuno, Yutaka; Kanou, Yasuhiko; Rogatcheva, Margarita B.; Imai, Tsuneo; Refetoff, Samuel; Seo, Hisao; Murata, Yoshiharu

doi:10.1530/eje.0.1500371

Cited by 14 publications

(24 citation statements)

References 29 publications

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“…In mice, two splice variants of Rcan2 that display distinct tissue-specific expression patterns have been identified (Mizuno et al, 2004): Rcan2-3 is expressed predominately in the brain, whereas Rcan2-1 is also expressed in other tissues, such as the heart and skeletal muscle. Recently, it was reported that loss of Rcan2 function in mice did not affect their linear growth (Bassett et al, 2012), but significantly ameliorated age-and dietinduced obesity by causing a reduction in food intake (Sun et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

A disputed evidence on obesity: comparison of the effects of Rcan2−/− and Rps6kb1−/− mutations on growth and body weight in C57BL/6J mice

Zhao

Gong

et al. 2016

J. Zhejiang Univ. Sci. B

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Abstract:It is widely accepted that body weight and adipose mass are tightly regulated by homeostatic mechanisms, in which leptin plays a critical role through hypothalamic pathways, and obesity is a result of homeostatic disorder. However, in C57BL/6J mice, we found that Rcan2 increases food intake and plays an important role in the development of age-and diet-induced obesity through a leptin-independent mechanism. RCAN2 was initially identified as a thyroid hormone (T3)-responsive gene in human fibroblasts. Expression of RCAN2 is regulated by T3 through the PI3K-Akt/PKB-mTOR-Rps6kb1 signaling pathway. Intriguingly, both Rcan2 −/− and Rps6kb1 −/− mutations were reported to result in lean phenotypes in mice. In this study we compared the effects of these two mutations on growth and body weight in C57BL/6J mice. We observed reduced body weight and lower fat mass in both Rcan2 −/− and Rps6kb1 −/− mice compared to the wild-type mice, and we reported other differences unique to either the Rcan2 −/− or Rps6kb1 −/− mice. Firstly, loss of Rcan2 does not directly alter body length; however, Rcan2 −/− mice exhibit reduced food intake. In contrast, Rps6kb1 −/− mice exhibit abnormal embryonic development, which leads to smaller body size and reduced food intake in adulthood. Secondly, when fed a normal chow diet, Rcan2 −/− mice weigh significantly more than Rps6kb1 −/− mice, but both Rcan2 −/− and Rps6kb1 −/− mice develop similar amounts of epididymal fat. On a high-fat diet, Rcan2 −/− mice gain body weight and fat mass at slower rates than Rps6kb1 −/− mice. Finally, using the double-knockout mice (Rcan2 −/− Rps6kb1 −/− ), we demonstrate that concurrent loss of Rcan2 and Rps6kb1 has an additive effect on body weight reduction in C57BL/6J mice. Our data suggest that Rcan2 and Rps6kb1 mutations both affect growth and body weight of mice, though likely through different mechanisms.

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Section: Introductionmentioning

confidence: 99%

A disputed evidence on obesity: comparison of the effects of Rcan2−/− and Rps6kb1−/− mutations on growth and body weight in C57BL/6J mice

Zhao

Gong

et al. 2016

J. Zhejiang Univ. Sci. B

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“…In the neonatal rat brain, expression of ZAKI-4 mRNA in cerebral cortex gradually increases with age but the increase is attenuated in hypothyroid pups [26]. Recently, we have also shown in the adult mouse brain that the expression of ZAKI-4 a mRNA is significantly decreased by hypothyroidism [19].…”

Section: Introductionmentioning

confidence: 79%

“…We have previously shown by Northern blot analysis that both ZAKI-4 a and b mRNAs are abundantly expressed in the brain [4,19]. The abundant expression of ZAKI-4 isoforms in brain is distinct among endogenous calcineurin inhibitors that contain an ISPPxSPP motif.…”

Section: Discussionmentioning

confidence: 97%

“…The rest of the amino acid sequences in the C terminus are identical among these isoforms. These ZAKI-4 isoforms are also expressed in mice and show a distinct tissue distribution [19]. Northern blot analysis of mRNAs extracted from mouse and human tissues revealed that the expression of ZAKI-4 a mRNA was limited in the brain, whereas the b isoform was detected not only in the brain, but also in other tissues such as heart and skeletal muscles [4,19].…”

Section: Introductionmentioning

confidence: 99%

“…These ZAKI-4 isoforms are also expressed in mice and show a distinct tissue distribution [19]. Northern blot analysis of mRNAs extracted from mouse and human tissues revealed that the expression of ZAKI-4 a mRNA was limited in the brain, whereas the b isoform was detected not only in the brain, but also in other tissues such as heart and skeletal muscles [4,19]. Since both ZAKI-4 a and b proteins contain the ISPPxSPP motif, which has been shown to be important for calcineurin inhibition [13], these isoforms seem to inhibit calcineurin activity and thus may play a role in the development and functions of the brain.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Spatial and Intracellular Distribution of the Endogenous Calcineurin-Inhibitory Proteins, ZAKI-4, in Mouse Brain

Hoshino

Takagishi

Kanou

et al. 2004

Acta Histochem. Cytochem

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Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

Park

Lee

et al. 2012

Toxicology and Applied Pharmacology

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Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR-/- mice, but not in hypothyroid PXR-/- mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR-/- hypothyroid mice, and this induction was abolished in CAR-/- mice and in and CAR-/- PXR-/- double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR-/- mice and lowest in WT and PXR-/- mice. Hypothyroid WT or PXR-/- mice survived chronic CBZ treatment, but all hypothyroid CAR-/- and CAR-/- PXR-/- mice died, with CAR-/-PXR-/- mice surviving longer than CAR-/- mice (12.3 ±3.3 days vs. 6.3 ±2.1 days, p=0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge.

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Genomic organization of mouse ZAKI-4 gene that encodes ZAKI-4 alpha and beta isoforms, endogenous calcineurin inhibitors, and changes in the expression of these isoforms by thyroid hormone in adult mouse brain and heart

Cited by 14 publications

References 29 publications

A disputed evidence on obesity: comparison of the effects of Rcan2−/− and Rps6kb1−/− mutations on growth and body weight in C57BL/6J mice

A disputed evidence on obesity: comparison of the effects of Rcan2−/− and Rps6kb1−/− mutations on growth and body weight in C57BL/6J mice

Spatial and Intracellular Distribution of the Endogenous Calcineurin-Inhibitory Proteins, ZAKI-4, in Mouse Brain

Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

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