Evidence for Cyclin D3 as a Novel Target of Rapamycin in Human T Lymphocytes

Hleb, Marija; Murphy, Shaun; Wagner, Eric F.; Hanna, Nazeeh; Sharma, Nishant; Park, Jungchen; Li, Xian Chang; Strom, Terry B.; Padbury, Jamés F.; Tseng, Yi‐Tang; Sharma, Surendra

doi:10.1074/jbc.m400638200

Cited by 41 publications

(34 citation statements)

References 67 publications

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“…(Fig 5). In line with these data, we and others have identified cyclin D3 to be an important target of Rap in malignant and normal lymphocytes (Decker et al, 2003;Hleb et al, 2004;Hipp et al, 2005). Importantly, cyclin D3 expression has been shown to be a predictive and prognostic factor in DLBCL (Filipits et al, 2002).…”

Section: Discussionsupporting

confidence: 53%

Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab

et al. 2006

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SummaryDiffuse large B‐cell lymphoma (DLBCL) is a common lymphoma entity. Although a significant amount of DLBCL patients can be cured with modern chemotherapeutic regimens, a substantial proportion of patients die because of progressive disease. Therefore, new therapeutic strategies are clearly needed. Inhibitors of mTOR [mammalian target of rapamycin (Rap)] represent a new class of antiproliferative drugs with applications as immunosuppressive and anticancer agents. Extensive safety data exist on the mTOR inhibitor RAD001, which is already approved as an immunosuppressant in organ transplant recipients. Rap and RAD001 inhibited cell cycle progression in DLBCL cells by inducing a G1 arrest without inducing apoptosis. Phosphorylation of the main targets of mTOR, p70 s6 kinase and 4‐EBP‐1 was reduced in cells cultured in the presence of RAD001. Cell cycle arrest was accompanied by reduced phosphorylation of the retinoblastoma protein (RB) as well as reduced expression of cyclin D3 and A in all cell lines. Although the effect of the chemotherapeutic agent vincristine (vin) was not enhanced by RAD001, rituximab‐induced cytotoxicity was augmented in the rituximab‐sensitive cell lines. mTOR inhibition is a promising therapeutic strategy in DLBCL by inducing a G1 arrest and augments rituximab‐induced cytotoxicity. Therefore, combination of these drugs might be an interesting new therapeutic approach in DLBCL patients.

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Section: Discussionsupporting

confidence: 53%

Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab

et al. 2006

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“…30,31 Rapamycin, an inhibitor of mTOR, may induce cell cycle arrest through inhibition of mTOR-p70S6K signaling and cyclin D3 expression. 32 In the present study, we observed the decreased expressions of cyclin D3, CDK4 and PCNA, and increased expressions of cell cycle inhibitor p27 and p21 in the PTEN delivery lungs (Figure 4). Several recent studies 33,34 have reported that PTEN entered into nucleus through passive diffusion is prominent in the G 0 /G 1 segment of cell cycle.…”

Section: Discussionmentioning

confidence: 64%

Urocanic acid-modified chitosan-mediated PTEN delivery via aerosol suppressed lung tumorigenesis in K-rasLA1 mice

Jin

et al. 2008

Cancer Gene Ther

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The low efficiency of conventional therapies in achieving long-term survival of lung cancer patients calls for development of novel options. Revisiting of aerosol gene delivery may provide an alternative for safe and effective treatment for lung cancer. In this study, imidazole ring-containing urocanic acid-modified chitosan (UAC) designed in the previous study was used as a gene carrier. The potential effects of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) on Akt-related signals and cell cycle regulation were evaluated. Aerosols of UAC-PTEN were delivered into K-ras LA1 lung cancer model mice through the nose-only inhalation system twice a week for total 4 weeks. Delivered PTEN suppressed lung tumor development significantly through nuclear complex formation between PTEN and p53, suppressing Akt-related signals as well as cell cycle regulation. Together, our results suggest that aerosol delivery of UAC-PTEN may be compatible with noninvasive in vivo gene therapy.

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“…Although T-ALL cells were efficiently eradicated when mTORC1 was inactivated in vivo, the reduction of CDK6 protein was not observed, suggesting that Cyclin D2 and D3 are major downstream targets of mTORC1. Some previous studies using rapamycin reported that the Cyclin D3 expression level is controlled by mTOR, but there were two possible mechanisms, i.e., translational regulation (31) and posttranslational regulation via the ubiquitin-proteasome pathway (32). In addition, 4E-BPs reportedly regulate mTORC1-mediated cell proliferation by translational control of Cyclin D3 in mouse embryonic fibroblasts (33).…”

Section: Inactivation Of Mtorc1 Prevents Oncogenic Kras-induced T-allmentioning

confidence: 99%

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

Hoshii

Kasada

Hatakeyama

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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mTOR is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants. Recent studies have shown that fine-tuning of the activity of mTOR complexes contributes to organogenesis and tumorigenesis. Although rapamycin, an allosteric mTOR inhibitor, is an effective immunosuppressant, the precise roles of mTOR complexes in early T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the development of both early T-cell progenitors and leukemia. Deletion of Raptor, an essential component of mTORC1, produced defects in the earliest development of T-cell progenitors in vivo and in vitro. Deficiency of Raptor resulted in cell cycle abnormalities in early T-cell progenitors that were associated with instability of the Cyclin D2/D3-CDK6 complexes; deficiency of Rictor, an mTORC2 component, did not have the same effect, indicating that mTORC1 and -2 control T-cell development in different ways. In a model of myeloproliferative neoplasm and T-cell acute lymphoblastic leukemia (T-ALL) evoked by Kras activation, Raptor deficiency dramatically inhibited the cell cycle in oncogenic Kras-expressing T-cell progenitors, but not myeloid progenitors, and specifically prevented the development of T-ALL. Although rapamycin treatment significantly prolonged the survival of recipient mice bearing T-ALL cells, rapamycin-insensitive leukemia cells continued to propagate in vivo. In contrast, Raptor deficiency in the T-ALL model resulted in cell cycle arrest and efficient eradication of leukemia. Thus, understanding the cell-contextdependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets.

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Evidence for Cyclin D3 as a Novel Target of Rapamycin in Human T Lymphocytes

Cited by 41 publications

References 67 publications

Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab

Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab

Urocanic acid-modified chitosan-mediated PTEN delivery via aerosol suppressed lung tumorigenesis in K-rasLA1 mice

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

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