Biomedical subjects

Kunihiko Takeyama

Publications and source records attributed to Kunihiko Takeyama.

6 recordsLinked to original sources

PubMed2006

Protein tyrosine phosphatase receptor-type O truncated (PTPROt) regulates SYK phosphorylation, proximal B-cell-receptor signaling, and cellular proliferation.

The strength and duration of B-cell-receptor (BCR) signaling depends upon the balance between protein tyrosine kinase (PTK) activation and protein tyrosine phosphatase (PTP) inhibition. BCR-dependent activation of the SYK PTK initiates downstream signaling events and amplifies the original BCR signal. Although BCR-associated SYK phosphorylation is clearly regulated by PTPs, SYK has not been identified as a direct PTP substrate. Herein, we demonstrate that SYK is a major substrate of a tissue-specific and developmentally regulated PTP, PTP receptor-type O truncated (PTPROt). PTPROt is a member of the PTPRO family (also designated GLEPP, PTP-Ø, PTP-oc, and PTPu2), a group of highly conserved receptor-type PTPs that are thought to function as tumor suppressor genes. The overexpression of PTPROt inhibited BCR-triggered SYK tyrosyl phosphorylation, activation of the associated adaptor proteins SHC and BLNK, and downstream signaling events, including calcium mobilization and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activation. PTPROt overexpression also inhibited lymphoma cell proliferation and induced apoptosis in the absence of BCR cross-linking, suggesting that the phosphatase modulates tonic BCR signaling.

Apoptosis↗

PubMed2006

Complete donor chimaerism of Langerhans cells in lymph node early after allogeneic bone marrow transplantation.

Host-derived Langerhans cells (LCs) are crucial antigen-presenting cells that cause graft-vs.-host disease after allogeneic haematopoietic stem cell transplantation (HSCT). However, chimaerism of LCs after allogeneic HSCT is largely unknown in humans. We here report a case that developed dermatopathic lymphadenitis accompanied by an accumulation of donor-derived LCs in the second month after allogeneic HSCT with reduced-intensity conditioning. This is the first case to show that donor LCs have the ability to migrate into draining lymph nodes and replace host LCs early after HSCT in humans.

Adult↗

PubMed2005

B-aggressive lymphoma family proteins have unique domains that modulate transcription and exhibit poly(ADP-ribose) polymerase activity.

BAL1 (B-aggressive lymphoma 1) was originally identified as a risk-related gene in diffuse large B-cell lymphoma. BAL1 encodes a nuclear protein with N-terminal macro domains and a putative C-terminal poly(ADP-ribose) polymerase (PARP) active site. Macro domains are sequences homologous to the non-histone region of histone macroH2A. Several lines of evidence suggest that these domains may modulate transcription, including a high concentration of histone macroH2A in the inactive X chromosome, direct interference with transcription factor binding in a positioned nucleosome, and structural similarity to DNA binding domains. Poly(ADP-ribosyl)ation is a critical post-translational modification that regulates chromatin configuration and transcription. In this report we describe two additional BAL family members, BAL2 and BAL3, with N-terminal macro domains and putative C-terminal PARP active sites and assess the function of these specific regions in BAL family members. Herein, we demonstrate that BAL macro domains repress transcription when tethered to a promoter. In addition, we show that BAL2 and BAL3, but not BAL1, exhibit PARP activity. In agreement with these data, BAL1 lacks several critical donor and acceptor residues that are conserved in the BAL2 and -3 PARP active sites. Of interest, BAL family members with inactive or functional PARP domains differed in their ability to repress transcription. BAL family members are the only described proteins with both PARP and macro domains, underscoring the potential functional significance of this unique combination.

Amino Acid Sequence↗

PubMed2004

PBSC mobilization.

Intentional recruitment of hematopoietic stem cells from bone marrow to peripheral blood is a clinical process termed peripheral blood stem cell (PSBC) mobilization. Mobilized PSBC has replaced bone marrow as the preferred source of stem cells for patients undergoing high-dose chemotherapy because of rapid and durable engraftment and reconstitution of functional bone marrow. Although the mechanism involved in the process of PBSC mobilization by cytokines is largely unknown, granulocyte colony-stimulating factor (G-CSF) alone or chemotherapy combined with GCSF is used as a mobilizing agent in current clinical practice. To date, G-CSF is the best cytokine for PBSC mobilization. However, there are some controversies in its efficacy (poor mobilizer) and safety (in allogeneic donors). Recent research progress has revealed some part of the mechanistic scenarios of PBSC mobilization and found promising candidates for the agents for PBSC mobilization. Until the research at molecular and cellular levels elucidates the precise mechanisms, collecting and comparing clinical observations is the best way to find more optimal condition for PBSC mobilization.

Cytokines↗

PubMed2003

The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity.

Members of the DTX (Deltex) family act as Notch signaling modifiers and may also regulate transcription through interactions with specific transcription factors. DTX proteins have a basic N terminus; a central proline-rich region; and a C-terminal RING finger domain, a motif often found in ubiquitin-protein isopeptide ligases (E3). Recently, we identified and characterized a unique diffuse large B-cell lymphoma risk-related gene named BAL (B aggressive lymphoma). Using a yeast two-hybrid screen for BAL-binding partners, we have now identified a novel protein termed BBAP (B-lymphoma- and BAL-associated protein). Although BBAP has a unique N terminus, the C-terminal region is highly homologous to that of DTX family members. Herein, we report that BBAP and the human family of DTX proteins (DTX1, DTX2, and DTX3) function as E3 ligases based on their capacity for self-ubiquitination. DTX family members homodimerize and heterodimerize in vivo, suggesting that physical interactions between various DTX family members modify E3 activity and/or substrate availability. Consistent with this idea, BBAP and DTX1 associate via their unique N termini, resulting in enhanced self-ubiquitination.

Amino Acid Sequence↗

PubMed2003

A dose-finding study of glycosylated G-CSF (Lenograstim) combined with CHOP therapy for stem cell mobilization in patients with non-Hodgkin's lymphoma.

BACKGROUND: Peripheral blood stem cell (PBSC) reinfusion has been widely used for hematopoietic reconstitution after high-dose chemotherapy. However, the optimal dose of granulocyte colony-stimulating factor (G-CSF) for PBSC mobilization in combination with chemotherapy for autograft remains unknown. METHODS: To find the optimal dose of glycosylated G-CSF (lenograstim) for PBSC mobilization in combination with chemotherapy for aggressive non-Hodgkin's lymphoma (NHL), we conducted a dose-finding study on 43 newly diagnosed patients who had unfavorable prognostic factors. They received four to six courses of cyclophosphamide, doxorubicin, vincristine and prednisolone combined with lenograstim every 2 weeks (biweekly CHOP therapy). PBSC apheresis was started after the third course of biweekly CHOP therapy. Lenograstim was given daily from day 3 until the day of the last apheresis. The optimum dose of lenograstim was assessed based on mobilization efficacy and safety profiles at a daily single dose of 2, 5 and 10 microg/kg for eight patients in each level. RESULTS: The collected number of CD34+ cells in the first apheresis products was higher in the 5 microg/kg group than in the 2 microg/kg group (median, 4.22 x 10(6) vs 2.49 x 10(6) CD34+ cells/kg, P = 0.051). The highest dose of 10 microg/kg (median, 2.99 x 10(6) CD34+ cells/kg) failed to show a dose dependence in PBSC mobilization. The efficacy and safety of the 5 microg/kg dose were further confirmed in an additional 19 patients. CONCLUSIONS: The present study suggests that the recommended dose of lenograstim for PBSC mobilization with CHOP therapy in untreated NHL is 5 microg/kg.

Adjuvants, Immunologic↗