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Ink4c is dispensable for tumor suppression in Myc-induced B-cell lymphomagenesis
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Heby)
Department of Biochemistry, St Jude Children’s Research Hospital, Memphis, TN, USA.
Department of Biochemistry, St Jude Children’s Research Hospital, Memphis, TN, USA.
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Nilsson)
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2007 (English)In: Oncogene, ISSN 0950-9232, Vol. 26, no 20, 2833-2839 p.Article in journal (Refereed) Published
Abstract [en]

p18(Ink4c) functions as a dedicated inhibitor of cyclin-D-dependent kinases. Loss of Ink4c predisposes mice to tumor development and, in a dose-dependent manner, complements the tumor-promoting effects of various oncogenes. We have now addressed whether Ink4c loss impacts B-cell tumor development in the Emu-Myc transgenic mouse, a model of human Burkitt lymphoma. Loss of one or both alleles did not influence the onset of lymphoma in Emu-Myc transgenics, and did not appreciably affect Myc's proliferative or apoptotic responses in precancerous B cells. Nevertheless, Ink4c loss modulated the effects of Myc-induced transformation by decreasing the frequency of Arf loss, an ordinarily common event in Emu-Myc-induced lymphomas.

Place, publisher, year, edition, pages
Basingstoke: Macmillan Press , 2007. Vol. 26, no 20, 2833-2839 p.
Keyword [en]
Animals, Apoptosis/genetics, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p16/genetics, Cyclin-Dependent Kinase Inhibitor p18/genetics/*physiology, Disease Progression, Gene Expression Regulation; Neoplastic, Genes; Immunoglobulin Heavy Chain, Lymphoma; B-Cell/*genetics/pathology/*prevention & control, Mice, Mice; Inbred C57BL, Mice; Transgenic, Oncogene Proteins; Fusion/genetics/physiology, Proto-Oncogene Proteins c-myc/genetics/*physiology
URN: urn:nbn:se:umu:diva-16700DOI: 10.1038/sj.onc.1210104PubMedID: 17099725OAI: diva2:156373
Available from: 2007-10-09 Created: 2007-10-09 Last updated: 2011-03-14Bibliographically approved
In thesis
1. The cell cycle regulators p18Ink4c and p19Ink4d: in vivo studies of their roles in tumorigenesis and development
Open this publication in new window or tab >>The cell cycle regulators p18Ink4c and p19Ink4d: in vivo studies of their roles in tumorigenesis and development
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Progression through the G1, S, G2 and M phases of the cell cycle is controlled by cyclin-dependent kinases (Cdks) and cyclins. These proteins form active Cdk:cyclin complexes that phosphorylate specific substrates. The Cdk:cyclin complexes of the G1/S transition regulate the progression of cells into the S phase by phosphorylating the retinoblastoma protein (Rb). This prevents Rb from sequestering E2F, a transcription factor that induces expression of genes required for DNA synthesis. This process is in part regulated by a family of Cdk inhibitors (CKIs) called the Ink4 family (Inhibitors of Cdk4). The Ink4 family of CKIs consists of four members; p16Ink4a, p15Ink4b, p18Ink4c and p19Ink4d, and they bind specifically to Cdk4 and Cdk6, thereby negatively regulating their kinase activities and cell cycle progression. Because of its cell cycle inhibitory role, p16Ink4a is frequently mutated or deleted in human cancer, whereas the other Ink4 genes are only occasionally altered in cancer. The overall aim of this thesis was to study the roles of p18Ink4c and p19Ink4d using in vivo models of cancer and embryonic development. In paper I, we analyzed the tumor spectrum in mice lacking p53, Ink4c and Ink4d. p53 is a tumor suppressor and one of the most frequently mutated genes in human cancer. Mice carrying mutated p53 alleles are highly tumor-prone but develop predominantly lymphomas. However, the combined loss of p53 and Ink4c (but not Ink4d) caused a shift in the tumor spectrum to increased incidences of hemangiomas and hemangiosarcomas, as well as appearance of medulloblastomas, a tumor of the cerebellum. These data, revealed in the absence of p53, suggest a cell-type specific tumor suppressing role for p18Ink4c. In paper II, loss of Ink4c was evaluated in another tumor-prone mouse model; the Eµ-Myc mouse. This is a transgenic mouse overexpressing c-Myc in B cells causing clonal B cell lymphomas. Surprisingly, precancerous B cells and lymphomas from Eµ-Myc mice exhibited elevated levels of p18Ink4c mRNA and protein despite high rates of proliferation. Moreover, loss of Ink4c in this model did not affect the rate of cell proliferation or the onset of tumor development. We conclude from these studies that Ink4c is not an important tumor suppressor of Myc-induced lymphomas. To gain insight into the role of Ink4 genes in early vertebrate development, the African clawed frog, Xenopus laevis, was analyzed for the presence of Ink4 homologs. Paper III describes the cloning and characterization of a gene homologous to Ink4d, Xl-Ink4d. This CKI is expressed throughout frog embryo development, making Xl-Ink4d the only CKI present during the cleavage stages of X. laevis. Antisense morpholino oligonucleotides directed against Xl-Ink4d were used to knock down the protein level of Xl-Ink4d during development. This resulted in defects in head tissues and reduced expression of Twist, a gene important for neural crest cell migration. We therefore propose that Xl-Ink4d is important for proper neural crest differentiation in the frog.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi (Teknisk-naturvetenskaplig fakultet), 2007. 48 p.
National Category
Biochemistry and Molecular Biology
urn:nbn:se:umu:diva-1357 (URN)978-91-7264-393-2 (ISBN)
Public defence
2007-10-12, Major Groove, 6L, Umeå universitet, Umeå, 09:00
Available from: 2007-09-19 Created: 2007-09-19 Last updated: 2011-03-14Bibliographically approved

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