Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Keiichi I. Nakayama is active.

Publication


Featured researches published by Keiichi I. Nakayama.


Cell | 1996

Mice Lacking p27Kip1 Display Increased Body Size, Multiple Organ Hyperplasia, Retinal Dysplasia, and Pituitary Tumors

Keiko Nakayama; Noriko Ishida; Michiko Shirane; Akira Inomata; Tomoaki Inoue; Nobuyuki Shishido; Ikuo Horii; Dennis Y. Loh; Keiichi I. Nakayama

SUMMARY Mice lacking p27(Kip1) have been created by gene targeting in embryonic stem cells. These mice are larger than the control animals, with thymus, pituitary, and adrenal glands and gonadal organs exhibiting striking enlargement. CDK2 activity is elevated about 10-fold in p27(-/-) thymocytes. Development of ovarian follicles seems to be impaired, resulting in female sterility. Similar to mice with the Rb mutation, the p27(-/-) mice often develop pituitary tumors spontaneously. The retinas of the mutant mice show a disturbed organization of the normal cellular layer pattern. These findings indicate that p27(Kip1) acts to regulate the growth of a variety of cells. Unexpectedly, the cell cycle arrest mediated by TGFbeta, rapamycin, or contact inhibition remained intact in p27(-/-) cells, suggesting that p27(Kip1) is not required in these pathways.


Science | 1995

Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice

Noboru Motoyama; Fanping Wang; Kevin A. Roth; Hirofumi Sawa; Keiichi I. Nakayama; Izumi Negishi; S Senju; Qing Zhang; S Fujii

bcl-x is a member of the bcl-2 gene family, which may regulate programmed cell death. Mice were generated that lacked Bcl-x. The Bcl-x-deficient mice died around embryonic day 13. Extensive apoptotic cell death was evident in postmitotic immature neurons of the developing brain, spinal cord, and dorsal root ganglia. Hematopoietic cells in the liver were also apoptotic. Analyses of bcl-x double-knockout chimeric mice showed that the maturation of Bcl-x-deficient lymphocytes was diminished. The life-span of immature lymphocytes, but not mature lymphocytes, was shortened. Thus, Bcl-x functions to support the viability of immature cells during the development of the nervous and hematopoietic systems.


Nature Reviews Cancer | 2006

Ubiquitin ligases: cell-cycle control and cancer

Keiichi I. Nakayama; Keiko Nakayama

A driving force of the cell cycle is the activation of cyclin-dependent kinases (CDKs), the activities of which are controlled by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors. Two ubiquitin ligases, the SKP1–CUL1–F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), are responsible for the specific ubiquitylation of many of these regulators. Deregulation of the proteolytic system might result in uncontrolled proliferation, genomic instability and cancer. Cumulative clinical evidence shows alterations in the ubiquitylation of cell-cycle regulators in the aetiology of many human malignancies. A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.


Cell Stem Cell | 2007

Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool

Kana Miyamoto; Kiyomi Y. Araki; Kazuhito Naka; Fumio Arai; Keiyo Takubo; Satoshi Yamazaki; Sahoko Matsuoka; Takeshi Miyamoto; Keisuke Ito; Masako Ohmura; Chen Chen; Kentaro Hosokawa; Hiromitsu Nakauchi; Keiko Nakayama; Keiichi I. Nakayama; Mine Harada; Noboru Motoyama; Toshio Suda; Atsushi Hirao

Hematopoietic stem cells (HSCs) are maintained in an undifferentiated quiescent state within a bone marrow niche. Here we show that Foxo3a, a forkhead transcription factor that acts downstream of the PTEN/PI3K/Akt pathway, is critical for HSC self-renewal. We generated gene-targeted Foxo3a(-/-) mice and showed that, although the proliferation and differentiation of Foxo3a(-/-) hematopoietic progenitors were normal, the number of colony-forming cells present in long-term cocultures of Foxo3a(-/-) bone marrow cells and stromal cells was reduced. The ability of Foxo3a(-/-) HSCs to support long-term reconstitution of hematopoiesis in a competitive transplantation assay was also impaired. Foxo3a(-/-) HSCs also showed increased phosphorylation of p38MAPK, an elevation of ROS, defective maintenance of quiescence, and heightened sensitivity to cell-cycle-specific myelotoxic injury. Finally, HSC frequencies were significantly decreased in aged Foxo3a(-/-) mice compared to the littermate controls. Our results demonstrate that Foxo3a plays a pivotal role in maintaining the HSC pool.


The EMBO Journal | 2000

Targeted disruption of Skp2 results in accumulation of cyclin E and p27Kip1, polyploidy and centrosome overduplication

Keiko Nakayama; Hiroyasu Nagahama; Yohji A. Minamishima; Masaki Matsumoto; Ikuo Nakamichi; Kyoko Kitagawa; Michiko Shirane; Ryosuke Tsunematsu; Tadasuke Tsukiyama; Noriko Ishida; Masatoshi Kitagawa; Keiichi I. Nakayama; Shigetsugu Hatakeyama

The ubiquitin–proteasome pathway plays an important role in control of the abundance of cell cycle regulators. Mice lacking Skp2, an F‐box protein and substrate recognition component of an Skp1–Cullin–F‐box protein (SCF) ubiquitin ligase, were generated. Although Skp2−/− animals are viable, cells in the mutant mice contain markedly enlarged nuclei with polyploidy and multiple centrosomes, and show a reduced growth rate and increased apoptosis. Skp2−/− cells also exhibit increased accumulation of both cyclin E and p27Kip1. The elimination of cyclin E during S and G2 phases is impaired in Skp2−/− cells, resulting in loss of cyclin E periodicity. Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27Kip1 is mediated by the SCFSkp2 ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators.


The EMBO Journal | 2004

Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7

Masayoshi Yada; Shigetsugu Hatakeyama; Takumi Kamura; Masaaki Nishiyama; Ryosuke Tsunematsu; Hiroyuki Imaki; Noriko Ishida; Fumihiko Okumura; Keiko Nakayama; Keiichi I. Nakayama

The F‐box protein Skp2 mediates c‐Myc ubiquitylation by binding to the MB2 domain. However, the turnover of c‐Myc is largely dependent on phosphorylation of threonine‐58 and serine‐62 in MB1, residues that are often mutated in cancer. We now show that the F‐box protein Fbw7 interacts with and thereby destabilizes c‐Myc in a manner dependent on phosphorylation of MB1. Whereas wild‐type Fbw7 promoted c‐Myc turnover in cells, an Fbw7 mutant lacking the F‐box domain delayed it. Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c‐Myc. Accumulation of c‐Myc was also apparent in mouse Fbw7−/− embryonic stem cells. These observations suggest that two F‐box proteins, Fbw7 and Skp2, differentially regulate c‐Myc stability by targeting MB1 and MB2, respectively.


The EMBO Journal | 1999

An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin.

Masatoshi Kitagawa; Shigetsugu Hatakeyama; Michiko Shirane; Masaki Matsumoto; Noriko Ishida; Kimihiko Hattori; Ikuo Nakamichi; Akira Kikuchi; Keiichi I. Nakayama; Keiko Nakayama

β‐catenin plays an essential role in the Wingless/Wnt signaling cascade and is a component of the cadherin cell adhesion complex. Deregulation of β‐catenin accumulation as a result of mutations in adenomatous polyposis coli (APC) tumor suppressor protein is believed to initiate colorectal neoplasia. β‐catenin levels are regulated by the ubiquitin‐dependent proteolysis system and β‐catenin ubiquitination is preceded by phosphorylation of its N‐terminal region by the glycogen synthase kinase‐3β (GSK‐3β)/Axin kinase complex. Here we show that FWD1 (the mouse homologue of Slimb/βTrCP), an F‐box/WD40‐repeat protein, specifically formed a multi‐molecular complex with β‐catenin, Axin, GSK‐3β and APC. Mutations at the signal‐induced phosphorylation site of β‐catenin inhibited its association with FWD1. FWD1 facilitated ubiquitination and promoted degradation of β‐catenin, resulting in reduced cytoplasmic β‐catenin levels. In contrast, a dominant‐negative mutant form of FWD1 inhibited the ubiquitination process and stabilized β‐catenin. These results suggest that the Skp1/Cullin/F‐box protein FWD1 (SCFFWD1)–ubiquitin ligase complex is involved in β‐catenin ubiquitination and that FWD1 serves as an intracellular receptor for phosphorylated β‐catenin. FWD1 also links the phosphorylation machinery to the ubiquitin–proteasome pathway to ensure prompt and efficient proteolysis of β‐catenin in response to external signals. SCFFWD1 may be critical for tumor development and suppression through regulation of β‐catenin protein stability.


Molecular Cell | 2002

CHIP Is Associated with Parkin, a Gene Responsible for Familial Parkinson's Disease, and Enhances Its Ubiquitin Ligase Activity

Yuzuru Imai; Mariko Soda; Shigetsugu Hatakeyama; Takumi Akagi; Tsutomu Hashikawa; Keiichi I. Nakayama; Ryosuke Takahashi

Unfolded Pael receptor (Pael-R) is a substrate of the E3 ubiquitin ligase Parkin. Accumulation of Pael-R in the endoplasmic reticulum (ER) of dopaminergic neurons induces ER stress leading to neurodegeneration. Here, we show that CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo. The amount of CHIP in the complex was increased during ER stress. CHIP promoted the dissociation of Hsp70 from Parkin and Pael-R, thus facilitating Parkin-mediated Pael-R ubiquitination. Moreover, CHIP enhanced Parkin-mediated in vitro ubiquitination of Pael-R in the absence of Hsp70. Furthermore, CHIP enhanced the ability of Parkin to inhibit cell death induced by Pael-R. Taken together, these results indicate that CHIP is a mammalian E4-like molecule that positively regulates Parkin E3 activity.


Molecular Cell | 2003

The F-Box Protein Skp2 Participates in c-Myc Proteosomal Degradation and Acts as a Cofactor for c-Myc-Regulated Transcription

Natalie von der Lehr; Sara Johansson; Siqin Wu; Fuad Bahram; Alina Castell; Cihan Cetinkaya; Per Hydbring; Ingrid Weidung; Keiko Nakayama; Keiichi I. Nakayama; Ola Söderberg; Tom K. Kerppola; Lars-Gunnar Larsson

The transcription regulatory oncoprotein c-Myc controls genes involved in cell growth, apoptosis, and oncogenesis. c-Myc is turned over very quickly through the ubiquitin/proteasome pathway. The proteins involved in this process are still unknown. We have found that Skp2 interacts with c-Myc and participates in its ubiquitylation and degradation. The interaction between Skp2 and c-Myc occurs during the G1 to S phase transition of the cell cycle in normal lymphocytes. Surprisingly, Skp2 enhances c-Myc-induced S phase transition and activates c-Myc target genes in a Myc-dependent manner. Further, Myc-induced transcription was shown to be Skp2 dependent, suggesting interdependence between c-Myc and Skp2 in activation of transcription. Moreover, Myc-dependent association of Skp2, ubiquitylated proteins, and subunits of the proteasome to a c-Myc target promoter was demonstrated in vivo. The results suggest that Skp2 is a transcriptional cofactor for c-Myc and indicates a close relationship between transcription activation and transcription factor ubiquitination.


Nature | 2011

SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction.

Hiroyuki Inuzuka; Shavali Shaik; Ichiro Onoyama; Darning Gao; Alan Tseng; Richard S. Maser; Bo Zhai; Lixin Wan; Alejandro Gutierrez; Alan W. Lau; Yonghong Xiao; Amanda L. Christie; Jeffrey Settleman; Steven P. Gygi; Andrew L. Kung; Thomas Look; Keiichi I. Nakayama; Ronald A. DePinho; Wenyi Wei

The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCFFBW7 (a SKP1–cullin-1–F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL.

Collaboration


Dive into the Keiichi I. Nakayama's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge