Dataset Information

Cks1 is required for tumor cell proliferation but not sufficient to induce hematopoietic malignancies.

ABSTRACT: The Cks1 component of the SCF(Skp2) complex is necessary for p27(Kip1) ubiquitylation and degradation. Cks1 expression is elevated in various B cell malignancies including Burkitt lymphoma and multiple myeloma. We have previously shown that loss of Cks1 results in elevated p27(Kip1) levels and delayed tumor development in a mouse model of Myc-induced B cell lymphoma. Surprisingly, loss of Skp2 in the same mouse model also resulted in elevated p27(Kip1) levels but exhibited no impact on tumor onset. This raises the possibility that Cks1 could have other oncogenic activities than suppressing p27(Kip1). To challenge this notion we have targeted overexpression of Cks1 to B cells using a conditional retroviral bone marrow transduction-transplantation system. Despite potent ectopic overexpression, Cks1 was unable to promote B cell hyperproliferation or B cell malignancies, indicating that Cks1 is not oncogenic when overexpressed in B cells. Since Skp2 overexpression can drive T-cell tumorigenesis or other cancers we also widened the quest for oncogenic activity of Cks1 by ubiquitously expressing Cks1 in hematopoetic progenitors. At variance with c-Myc overexpression, which caused acute myeloid leukemia, Cks1 overexpression did not induce myeloproliferation or leukemia. Therefore, despite being associated with a poor prognosis in various malignancies, sole Cks1 expression is insufficient to induce lymphoma or a myeloproliferative disease in vivo.

SUBMITTER: Kratzat S

PROVIDER: S-EPMC3356264 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cks1 is required for tumor cell proliferation but not sufficient to induce hematopoietic malignancies.

Kratzat Susanne S Nikolova Viktoriya V Miething Cornelius C Hoellein Alexander A Schoeffmann Stephanie S Gorka Oliver O Pietschmann Elke E Illert Anna-Lena AL Ruland Jürgen J Peschel Christian C Nilsson Jonas J Duyster Justus J Keller Ulrich U

PloS one 20120518 5

The Cks1 component of the SCF(Skp2) complex is necessary for p27(Kip1) ubiquitylation and degradation. Cks1 expression is elevated in various B cell malignancies including Burkitt lymphoma and multiple myeloma. We have previously shown that loss of Cks1 results in elevated p27(Kip1) levels and delayed tumor development in a mouse model of Myc-induced B cell lymphoma. Surprisingly, loss of Skp2 in the same mouse model also resulted in elevated p27(Kip1) levels but exhibited no impact on tumor ons ...[more]

PMID: 22624029

Similar Datasets

Project description:BackgroundGranulocyte colony-stimulating factor (G-CSF)-mediated mobilization of hematopoietic stem cells (HSCs) is a well-established method to prepare HSCs for transplantation nowadays. A sufficient number of HSCs is critical for successful HSC transplantation. However, approximately 2-6% of healthy stem cell donors are G-CSF-poor mobilizers for unknown reasons; thus increasing the uncertainties of HSC transplantation. The mechanism underlining G-CSF-mediated HSC mobilization remains elusive, so detailed mechanisms and an enhanced HSC mobilization strategy are urgently needed. Evidence suggests that P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) are one of the cell-cell adhesion ligand-receptor pairs for HSCs to keep contacting bone marrow (BM) stromal cells before being mobilized into circulation. This study hypothesized that blockage of PSGL-1 and P-selectin may disrupt HSC-stromal cell interaction and facilitate HSC mobilization.MethodsThe plasma levels of soluble P-selectin (sP-sel) before and after G-CSF administration in humans and male C57BL/6J mice were analyzed using enzyme-linked immunosorbent assay. Male mice with P-selectin deficiency (Selp-/-) were further employed to investigate whether P-selectin is essential for G-CSF-induced HSC mobilization and determine which cell lineage is sP-sel derived from. Finally, wild-type mice were injected with either G-CSF or recombinant sP-sel to investigate whether sP-sel alone is sufficient for inducing HSC mobilization and whether it accomplishes this by binding to HSCs and disrupting their interaction with stromal cells in the BM.ResultsA significant increase in plasma sP-sel levels was observed in humans and mice following G-CSF administration. Treatments of G-CSF induced a decrease in the level of HSC mobilization in Selp-/- mice compared with the wild-type (Selp+/+) controls. Additionally, the transfer of platelets derived from wild-type mice can ameliorate the defected HSC mobilization in the Selp-/- recipients. G-CSF induces the release of sP-sel from platelets, which is sufficient to mobilize BM HSCs into the circulation of mice by disrupting the PSGL-1 and P-selectin interaction between HSCs and stromal cells. These results collectively suggested that P-selectin is a critical factor for G-CSF-induced HSC mobilization.ConclusionssP-sel was identified as a novel endogenous HSC-mobilizing agent. sP-sel injections achieved a relatively faster and more convenient regimen to mobilize HSCs in mice than G-CSF. These findings may serve as a reference for developing and optimizing human HSC mobilization in the future.

Dataset Information

Cks1 is required for tumor cell proliferation but not sufficient to induce hematopoietic malignancies.

Publications

Cks1 is required for tumor cell proliferation but not sufficient to induce hematopoietic malignancies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets