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1.
Oncogene ; 20(25): 3247-57, 2001 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-11423974

RESUMO

Protein kinase CK2 is a ubiquitous and evolutionarily conserved serine/threonine kinase that is upregulated in many human cancers and can serve as an oncogene in lymphocytes. Recently, we have demonstrated that CK2 potentiates Wnt/beta-catenin signaling in mammary epithelial cells. To determine whether CK2 overexpression contributes to mammary tumorigenesis, we have performed comparative studies of human and rat breast cancer specimens and we have engineered transgenic mice with dysregulated expression of CK2alpha in the mammary gland. We find that CK2 is highly expressed in human breast tumor specimens and in carcinogen-induced rat mammary tumors. Overexpression of CK2alpha in the mammary gland of transgenic mice, under control of the MMTV-LTR, causes hyperplasia and dysplasia of the female mammary gland. Thirty per cent of the female MMTV-CK2alpha transgenic mice develop mammary adenocarcinomas at a median of 23 months of age, often associated with Wnt pathway activation, as evidenced by upregulation of beta-catenin protein. NF-kappaB activation and upregulation of c-Myc also occur frequently. Thus, in mice, rats, and humans, dysregulated expression of CK2 is associated with and is capable of contributing to mammary tumorigenesis. Targeted inhibition of CK2 could be useful in the treatment of breast cancer.


Assuntos
Adenocarcinoma/etiologia , Neoplasias da Mama/etiologia , Transformação Celular Neoplásica , Neoplasias Mamárias Animais/etiologia , Proteínas Serina-Treonina Quinases/biossíntese , Transativadores , Proteínas de Peixe-Zebra , Idade de Início , Animais , Caseína Quinase II , Proteínas do Citoesqueleto/metabolismo , Feminino , Doença da Mama Fibrocística , Humanos , Hiperplasia , Lactação , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/induzido quimicamente , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Proteínas Wnt , beta Catenina
2.
Cancer Res ; 61(9): 3810-8, 2001 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-11325857

RESUMO

Nuclear factor-kappaB (NF-kappaB)/Rel transcription factors regulate genes that control cell proliferation, survival, and transformation. In normal breast epithelial cells, NF-kappaB/Rel proteins are mainly sequestered in the cytoplasm bound to one of the specific inhibitory IkappaB proteins, whereas in breast cancers they are activated aberrantly. Human breast tumor cell lines, carcinogen-transformed mammary epithelial cells, and the majority of primary human or rodent breast tumor tissue samples express constitutively high levels of nuclear NF-kappaB/REL: To begin to understand the mechanism of this aberrant NF-kappaB/Rel expression, in this study we measured the activity of the major kinases implicated in regulation of IkappaB stability, namely IKKalpha, IKKbeta, and protein kinase, CK2 (formerly casein kinase II). Hs578T, D3-1, and BP-1 breast cancer cell lines displayed higher levels of IKKalpha, IKKbeta, and CK2 activity than untransformed MCF-10F mammary epithelial cells. Inhibition of IKK activity upon expression of dominant negative kinases or of CK2 activity by treatment with selective inhibitors decreased NF-kappaB/Rel activity in breast cancer cells. Inactivation of the IkappaB kinase complex in Hs578T cells via expression of a dominant negative IKKgamma/NF-kappaB essential modulator/IKK-associated protein 1 reduced soft agar colony growth. Thus, the aberrant expression of CK2 or IKK kinases promotes increased nuclear levels of NF-kappaB/Rel and transformation of breast cancer cells. Furthermore, primary human breast cancer specimens that displayed aberrant constitutive expression of NF-kappaB/Rel were found to exhibit increased CK2 and/or IKK kinase activity. These observations suggest these kinases play a similar role in an intracellular signaling pathway that leads to the elevated NF-kappaB/Rel levels seen in primary human mammary tumors and, therefore, represent potential therapeutic targets in the treatment of patients with breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias da Mama/patologia , Caseína Quinase II , Adesão Celular/fisiologia , Divisão Celular/fisiologia , Sobrevivência Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Ativação Enzimática , Humanos , Quinase I-kappa B , NF-kappa B/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Células Tumorais Cultivadas
3.
Mol Cell Biochem ; 227(1-2): 153-65, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11827167

RESUMO

Breast cancer is a major cause of cancer death in women, and the genetic abnormalities leading to the common sporadic forms of the disease are still under active investigation. CK2 has been reported to be upregulated in human breast cancer, which these studies confirm; CK2 is also upregulated in rat carcinogen-induced breast tumors. Transgenic mice overexpressing CK2alpha in the mammary gland develop mammary hyperplasia, dysplasia, and eventually adenocarcinomas, demonstrating that dysregulated expression of CK2 can contribute to transformation of the mammary epithelium. These mammary tumors have evidence of activation of the Wnt and NFkappaB pathways and upregulation of c-Myc. CK2 is capable of phosphorylating the key signaling molecule in the Wnt pathway, the transcriptional cofactor beta-catenin, and regulating its turnover. CK2 is known to phosphorylate IkappaB and thereby regulate basal NFkappaB levels; in the mammary cell lines and tumors, CK2 activity correlates with NFkappaB levels and inhibition of CK2 downregulates NFkappaB. Thus, CK2 may promote breast cancer through dysregulation of key pathways of transcriptional control in the mammary epithelium, and inhibition of CK2 has a potential role in the treatment of breast and other cancers.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias Mamárias Animais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas de Peixe-Zebra , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Apigenina , Western Blotting , Caseína Quinase II , DNA Complementar/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo , Flavonoides/farmacologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias Experimentais , Fosforilação , Testes de Precipitina , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ratos , Transdução de Sinais , Fatores de Tempo , Transcrição Gênica , Regulação para Cima , Proteínas Wnt
4.
J Biol Chem ; 275(29): 22245-54, 2000 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-10801845

RESUMO

Human SIX1 (HSIX1) is a member of the Six class of homeodomain proteins implicated in muscle, eye, head, and brain development. To further understand the role of HSIX1 in the cell cycle and cancer, we developed an HSIX1-specific antibody to study protein expression at various stages of the cell cycle. Our previous work demonstrated that HSIX1 mRNA expression increases as cells exit S phase and that overexpression of HSIX1 can attenuate a DNA damage-induced G(2) cell cycle checkpoint. Overexpression of HSIX1 mRNA was observed in 44% of primary breast cancers and 90% of metastatic lesions. Now we demonstrate that HSIX1 is a nuclear phosphoprotein that becomes hyperphosphorylated at mitosis in both MCF7 cells and in Xenopus extracts. The pattern of phosphorylation observed in mitosis is similar to that seen by treating recombinant HSIX1 with casein kinase II (CK2) in vitro. Apigenin, a selective CK2 inhibitor, diminishes interphase and mitotic phosphorylation of HSIX1. Treatment of MCF7 cells with apigenin leads to a dose-dependent arrest at the G(2)/M boundary, implicating CK2, like HSIX1, in the G(2)/M transition. HSIX1 hyperphosphorylated in vitro by CK2 loses its ability to bind the MEF3 sites of the aldolase A promoter (pM), and decreased binding to pM is observed during mitosis. Because CK2 and HSIX1 have both been implicated in cancer and in cell cycle control, we propose that HSIX1, whose activity is regulated by CK2, is a relevant target of CK2 in G(2)/M checkpoint control and that both molecules participate in the same pathway whose dysregulation leads to cancer.


Assuntos
Ciclo Celular , Proteínas de Homeodomínio/metabolismo , Sequência de Aminoácidos , Animais , Caseína Quinase II , Humanos , Dados de Sequência Molecular , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Transdução de Sinais , Xenopus
5.
Mol Cell Biochem ; 191(1-2): 65-74, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10094394

RESUMO

Protein kinase CK2 (casein kinase II) is a serine-threonine protein kinase with a wide range of substrates, many of which are involved in cell cycle regulation. CK2 activity is elevated in a variety of human tumors and we have used a transgenic mouse model to demonstrate that dysregulated expression of CK2 can induce lymphoma. Thus, CK2 fulfills the definition of an oncogene: A mutated, dysregulated, or mis-expressed gene that contributes to cancer in a dominant fashion. CK2 cooperates in transforming cells with other lymphoid oncogenes such as myc and tal-1, and here we show cooperativity with loss of the tumor suppressor gene p53. To understand more about the physiological and pathological role of CK2, we are cloning the murine CK2alpha' cDNA and gene. CK2alpha' will be used to generate transgenic and knockout mice and the regulatory elements for gene expression will be analyzed.


Assuntos
Oncogenes , Proteínas Serina-Treonina Quinases/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Caseína Quinase II , DNA Complementar , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
6.
J Immunol ; 161(10): 5164-70, 1998 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-9820486

RESUMO

MRL-lpr/lpr mice have a Fas receptor mutation that leads to abnormalities of apoptosis, lymphoproliferation, and a lupus-like autoimmune disease associated with the production of autoantibodies. Other than Fas pathway defects, little is known about molecular abnormalities that predispose to autoimmunity. Protein kinase CK2 (also termed casein kinase II), a serine-threonine protein kinase whose targets include many critical regulators of cellular growth, is highly expressed in a lymphoproliferative disease of cattle and in many human cancers. Overexpression of the CK2alpha catalytic subunit in lymphocytes of transgenic mice leads to T cell lymphoma. We hypothesized that CK2 dysregulation and Fas mutation might cooperatively augment lymphocyte proliferation and transformation. We find that in MRL-lpr/lpr mice bearing the CK2alpha transgene, the lymphoproliferative process is dramatically exacerbated, as these mice develop massive splenomegaly and lymphadenopathy by 12 wk of age in association with increased autoantibody production and accelerated renal disease. The lymphoid organs are filled with the unusual B220+CD4-CD8- T cells typically seen in MRL-lpr/lpr mice, not the B220-CD4+CD8+ or B220-CD4-CD8+ T cells typically seen in CK2a transgenic lymphomas. The T cells do not fulfill the criteria for transformation, as they are polyclonal and not transplantable or immortal in cell culture. Thus, although the lpr lymphoproliferative and autoimmune syndrome is potentiated by the presence of the CK2a transgene, this combination of apoptotic and proliferative abnormalities appears to be insufficient to transform lymphoid cells.


Assuntos
Doenças Autoimunes/genética , Transtornos Linfoproliferativos/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Transgenes/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Antígenos CD4/análise , Antígenos CD8/análise , Caseína Quinase II , Regulação da Expressão Gênica/imunologia , Heterozigoto , Homozigoto , Antígenos Comuns de Leucócito/análise , Doenças Linfáticas/genética , Doenças Linfáticas/imunologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Camundongos Transgênicos , Esplenomegalia/genética , Esplenomegalia/imunologia , Subpopulações de Linfócitos T/imunologia
7.
Oncogene ; 16(23): 2965-74, 1998 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-9662328

RESUMO

Protein kinase CK2 (casein kinase II) is a serine-threonine protein kinase with many substrates, some of which are involved in cell cycle regulation. CK2 activity is elevated in human solid tumors and leukemia, and dysregulated expression of CK2 induces lymphoma in transgenic mice. Mice that are deficient in p53 also develop lymphomas, and p53 activity may be regulated by CK2 phosphorylation. Here we demonstrate that CK2alpha transgenic mice partially or completely deficient in p53 develop thymic lymphomas at a markedly accelerated rate when compared to p53-deficient mice lacking the transgene. Lymphomas originating from CK2alpha transgenic mice that are heterozygous for p53 generally lose the wild type p53 allele, indicating that loss of p53 is an important step in tumor progression. Moreover, though lymphomas occur as early as 3 weeks of age in the transgenic mice that are nullizygous for p53, they are still monoclonal, indicating that additional stochastic mutations are required for their development. These lymphomas express high levels of myc mRNA and frequently ectopically express Lmo-2, a transcription factor involved in human T cell acute lymphocytic leukemia. The p53-null CK2alpha transgenic lymphomas grow rapidly but are highly prone to apoptosis, suggesting that transformation occurs through synergistic dysregulation of cell cycle control induced by misexpression of CK2 and loss of function of p53.


Assuntos
Linfoma de Células T/etiologia , Proteínas Serina-Treonina Quinases/fisiologia , Neoplasias do Timo/etiologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Caseína Quinase II , Dosagem de Genes , Imunofenotipagem , Linfoma de Células T/enzimologia , Linfoma de Células T/genética , Linfoma de Células T/patologia , Camundongos , Camundongos Transgênicos , Mutagênese , Proteínas Serina-Treonina Quinases/genética , Timo/patologia , Neoplasias do Timo/enzimologia , Neoplasias do Timo/genética , Neoplasias do Timo/patologia , Proteína Supressora de Tumor p53/genética
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