Biomedical subjects

Yasuhiko Okimura

Publications and source records attributed to Yasuhiko Okimura.

22 records · Page 2Linked to original sources

PubMed2002

Novel function of the transactivation domain of a pituitary-specific transcription factor, Pit-1.

Pit-1 stimulates the expression of growth hormone, prolactin, and thyrotropin beta subunit genes. Consequently, abnormality of the Pit-1 gene results in combined pituitary hormone deficiency (CPHD). In this study, we analyzed the function of Pit-1 with a mutation (proline to leucine at codon 24) in the transactivation domain, P24L, which has a normal POU domain important for binding to DNA, because this mutation had been reported in a patient with CPHD. We found that codon 24 proline in the transactivation domain as well as the POU domain of Pit-1 was crucial to recruit coactivator CREB-binding protein (CBP) in the cultured cells. P24L completely lost the responsiveness to cAMP to stimulate the expression of the Pit-1-targeted genes. Furthermore, CBP and Pit-1, but not P24L, markedly enhanced the expression of the Pit-1-targeted gene to cAMP, and adenovirus E1a that binds to CBP and abrogates its function blocked the induction by cAMP of Pit-1-stimulated gene transcription in the pituitary-derived GH3 cells. These results suggest that CBP and proline at codon 24 in the transactivation domain of Pit-1 are important for the cAMP-induced activation of Pit-1-targeted genes. However, P24L maintained basal transcriptional activity, suggesting that CBP is unlikely to be an essential coactivator for Pit-1.

Animals↗

PubMed2002

A novel heterozygous T51I mutation of growth hormone receptor is not associated with short stature.

A novel missense mutation of the growth hormone receptor (GHR) gene was identified in a Japanese short boy with GH insensitivity. The analysis of the GHR gene revealed a novel heterozygous T51I mutation in exon 4. To clarify the effect of this mutation on GH signaling, the mutant GHR was expressed in CHO cells and its functional properties were investigated. The signal transducer and activator of transcription 5 (STAT5)-mediated transcriptional activation in mutant GHR (GHR-T51I)-expressing cells was significantly reduced as compared with wild-type GHR (GHR-wt)-expressing cells. The CHO cells co-expressing the GHR-T51I and GHR-wt, however, revealed no functional differences as compared with cells expressing GHR-wt alone, indicating that the T51I mutation does not exert the dominant negative effect. In addition, the mother and the elder brother of the proband, whose heights were normal, possessed the same heterozygous mutation. These results suggest that the heterozygous T51I mutation of GHR does not inhibit the signal transduction of GH and is not responsible for GH insensitivity.

Amino Acid Sequence↗

PubMed2002

Adult growth hormone deficiency in Japan: results of investigation by questionnaire.

Adult GH deficiency (AGHD) has been established as a syndrome associated with various metabolic disturbances such as hyperlipidemia, impaired glucose tolerance and protein catabolism, in addition to changes in body composition such as increased visceral fat, decreased muscle mass and bone density. We investigated the clinical findings, complications and prognosis of AGHD in Japan. The questionnaire was sent to various expert facilities of endocrinology and metabolism to gather cross-sectional information as well as longitudinal follow-up data on adult patients with hypopituitarism. We received answers on 422 subjects, of which number the GH stimulation test was performed in only 63% of them. An age- and sex-matched group of 259 adults with hypopituitarism (125 male and 134 female subjects) was finally selected for this investigation. Of them 185 subjects (81 male and 104 females) were diagnosed as AGHD with plasma peak GH levels less than 3 ng/ml after GH stimulation test. Male adult patients with GHD had significantly lower ratio of smoking and drinking in their life style compared with those without GHD. Male adult patients with GHD revealed significantly higher BMI on physical examination, and significantly higher plasma ALT, AST, total cholesterol, and LDL cholesterol in blood chemistry compared with those without GHD (P < 0.05). Though patients with ischemic heart disease were more frequent in female patients than male patients, the rate of frequency was not different between female adult patients with and without GHD. Clinical characteristics found in especially male adult patients with GHD in Japan were consistent with findings reported so far in foreign countries. However, consequent complications such as atherosclerosis seemed less severe than expected. Moreover, GH stimulation test for the diagnosis of AGHD as well as clinical test to perform when AGHD was suspected is still less frequently carried out. Therefore, the clinical outcome of AGHD in our country requires further investigation.

Adult↗

PubMed2001

Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells.

Ghrelin was identified in the stomach as an endogenous ligand specific for the growth hormone secretagogue receptor (GHS-R). GHS-R is found in various tissues, but its function is unknown. Here we show that GHS-R is found in hepatoma cells. Exposure of these cells to ghrelin caused up-regulation of several insulin-induced activities including tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1, mitogen-activated protein kinase activity, and cell proliferation. Unlike insulin, ghrelin inhibited Akt kinase activity as well as up-regulated gluconeogenesis. These findings raise the possibility that ghrelin modulates insulin activities in humans.

Animals↗