Biomedical subjects

Aya Sasaki

Publications and source records attributed to Aya Sasaki.

7 recordsLinked to original sources

PubMed2006

Social context-dependent singing-regulated dopamine.

Like the mammalian striatum, the songbird striatum receives dense dopaminergic input from the midbrain ventral tegmental area-substantia nigra pars compacta complex. The songbird striatum also contains a unique vocal nucleus, Area X, which has been implicated in song learning and social context-dependent song production. Area X shows increased neural firing and activity-dependent gene expression when birds sing, and the level of activation is higher and more variable during undirected singing relative to directed singing to other birds. Here we show in the first report of in vivo microdialysis in awake, behaving songbirds that singing is associated with increased dopamine levels in Area X. Dopamine levels are significantly higher with directed relative to undirected singing. This social context-dependent difference in dopamine levels requires the dopamine transporter, because local in vivo blockade of the transporter caused dopamine levels for undirected singing to increase to levels similar to that for directed singing, eliminating the social context-dependent difference. The increase in dopamine is presumably depolarization and vesicular release dependent, because adding of high K+ increased and removal of Ca2+ increased and decreased extracellular DA levels. Our findings implicate DA and molecules that control DA kinetics in singing behavior and social context-dependent brain function.

Animal Communication↗

PubMed2005

Combined expression of p53, cyclin D1 and epidermal growth factor receptor improves estimation of prognosis in curatively resected oral cancer.

p53, cyclin D1 and epidermal growth factor receptor (EGFR) are molecular markers that regulate the cell cycle or cell growth and play important roles in tumor development and progression. In this study, we examined the impact of immunohistochemical expression of these markers on tumor progression in 140 oral cancers. p53, cyclin D1 and EGFR were expressed in 64 cases (46%), 54 cases (39%) and 54 cases (39%), respectively, but there was no inter-relationship between any two of these markers. In the association of these markers with clinicopathological features, EGFR expression alone was significantly associated with poor differentiation (P=0.0008) and invasive growth pattern (P=0.0003). Any of these markers, including EGFR, had no significant impact on survival. Coexpression of all these markers, however, was significantly associated with invasive growth pattern (P=0.0149) and shortened survival (P=0.0181), and was a significant and independent unfavorable prognostic factor (P=0.0002), along with tumor size (P=0.0040), nodal metastasis (P=0.0137) and growth pattern (P=0.0017) in a multivariate analysis. Simultaneous coexpression of these markers in oral cancers might prove to be a useful indicator for identification of low- or high-risk patients.

Adult↗

PubMed2005

RumMAGE-D the members: structure and function of a new adaptor family of MAGE-D proteins.

MAGE genes were first described as cancer-testis antigens, which are silenced in normal adult tissues but aberrantly expressed in tumor cells. The short peptides, derived from the degradation of MAGE transcripts, are the source of antigens that cause tumor rejection reactions when presented in the context of major histocompatibility complex. The recent discovery of a subset of genes that contain the structurally conserved MAGE homology domain (MHD) has accelerated the investigation into the normal function of MAGE genes. This new type of MAGE gene is normally expressed in embryonal and adult tissue, especially the brain. MAGE-D1, also known as NRAGE or Dlxin-1, functions as an adaptor protein that mediates multiple signaling pathways, including NGFR (p75NTR) and UNC5H1-induced apoptosis and Dlx/Msx-mediated transcription. Loss of a different MAGE family member, Necdin, which works as a cell cycle regulator, may play a role in the pathogenesis of Prader-Willi syndrome, a neurobehavioral disorder. In this article, the authors discuss recent findings concerning the structure and function of new MAGE genes, primarily focusing on MAGE-D1. Because some MAGE-D subfamily proteins share significant homology within the MHD, these recent discoveries on MAGE-D1 may give insight into the function of other MAGE-D proteins.

Adaptor Proteins, Signal Transducing↗

PubMed2005

A patient with TP53 germline mutation developed Bowen's disease and myelodysplastic syndrome with myelofibrosis after chemotherapy against ovarian cancer.

Here we report a case of myelodysplastic syndrome (MDS) with myelofibrosis associated with Bowen's disease. A female patient had undergone an operation and chemotherapy for ovarian cancer when she was 65 years old, and she developed MDS at the age of 70 years old. PCR-single strand conformation polymorphism (SSCP) analysis of peripheral blood mononuclear cells, a Bowen's disease lesion, and normal skin showed an abnormal peak in TP53 exon5. Direct sequencing revealed that they all had missense mutation in codon 175 (G to A) of arginine switched to histidine, suggesting a germline mutation of TP53. It was speculated that p53 function was lost by TP53 germline mutation with the loss of a wild type allele induced by the chemotherapy against ovarian cancer, leading to the development of MDS. No therapeutic effects of low dose melphalan or cyclosporine A on MDS were observed, however one month of 30 mg/day prednisolone administration induced a hematological response.

Aged↗

PubMed2003

The receptor tyrosine kinase Ror2 associates with the melanoma-associated antigen (MAGE) family protein Dlxin-1 and regulates its intracellular distribution.

The mammalian Ror family receptor tyrosine kinases, Ror1 and Ror2, play crucial roles in developmental morphogenesis. Although the functions of Ror1 and Ror2 are redundant, Ror2 exhibits more specific functions during development. We show that when expressed in mammalian cells, Ror2, but not Ror1, associates with the melanoma-associated antigen (MAGE) family protein, Dlxin-1, which is known to bind to the homeodomain proteins Msx2 and Dlx5 and regulate their transcriptional functions. This association requires the cytoplasmic C-terminal region of Ror2, containing proline-rich and serine/threonine-rich domains, and the C-terminal necdin homology domain of Dlxin-1. Interestingly, the cytoplasmic C-terminal region of Ror2 is missing in patients with brachydactyly type B. Interestingly, transient expression and immunohistochemical analyses reveal that both Dlxin-1 and Msx2 are co-localized in the nuclei in the absence of Ror2. In the presence of Ror2, Dlxin-1 is co-localized with Ror2 at the membranous compartments and Msx2 is retained in the nuclei. It was also found that the majority of cellular Dlxin-1 is retained in the membrane fractions of wild-type but not Ror2-/- mouse embryonic fibroblasts. Furthermore, we show that transcriptional activity of Msx2, irrespective of Ror2 kinase activity, is regulated by ectopic expression of Ror2 using a reporter plasmid containing the WIP element. Thus, Ror2 sequesters Dlxin-1 in membranous compartments, thereby affecting the transcriptional function of Msx2.

Amino Acid Sequence↗

PubMed2002

A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein, Dlxin-1.

Msx2 and Dlx5 are homeodomain proteins that play an important role in osteoblast differentiation and whose expression is induced by bone morphogenetic proteins. Recently we have identified a novel protein, Dlxin-1, that associates with these homeodomain proteins and regulates Dlx5-dependent transcriptional function (Masuda, Y., Sasaki, A., Shibuya, H., Ueno, N., Ikeda, K., and Watanabe, K. (2001) J. Biol. Chem. 276, 5331-5338). In an attempt to elucidate the molecular function of Dlxin-1, two closely related RING finger proteins, Praja1 and Neurodap-1, were isolated by yeast two-hybrid screening using the C-terminal necdin homology domain of Dlxin-1 as bait. Glutathione S-transferase pull-down and immunoprecipitation/Western blotting assays following co-transfection of Dlxin-1 and Praja1 revealed that Praja1 binds to the C-terminal necdin homology domain of Dlxin-1 in vitro and in vivo, respectively. Overexpression of Praja1 caused a decrease in Dlxin-1 protein level, which was reversed when a proteasome inhibitor was added. Overexpression of Praja1 with a mutation in the RING finger inhibited the decrease in Dlxin-1 protein, pointing to the importance of ubiquitin-protein isopeptide ligase (E3) activity associated with RING finger. Wild-type Praja1, but not its RING finger mutant, promoted ubiquitination of Dlxin-1 in vivo. Finally, expression of Praja1 down-regulated Dlx5-dependent transcriptional activity in a GAL4-dependent assay. These results suggest that Praja1 regulates the transcription function of the homeodomain protein Dlx5 by controlling the stability of Dlxin-1 via an ubiquitin-dependent degradation pathway.

Antigens, Neoplasm↗

PubMed2002

Temporal integration as a function of signal and gap intensity in rats (Rattus norvegicus) and pigeons (Columba livia).

Previous data suggest that rats (Rattus norvegicus) and pigeons (Columba livia) use different interval-timing strategies when a gap interrupts a to-be-timed signal: Rats stop timing during the gap, and pigeons reset their timing mechanism after the gap. To examine whether the response rule is controlled by an attentional mechanism dependent on the characteristics of the stimuli, the authors manipulated the intensity of the signal and gap when rats and pigeons timed in the gap procedure. Results suggest that both rats and pigeons stop timing during a nonsalient gap and reset timing after a salient gap. These results also suggest that both species use similar interval-timing mechanisms, influenced by nontemporal characteristics of the signal and gap.

Animals↗