Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1- infected cells

Francisco Santiago, Elizabeth Clark, Siewyen Chong, Carlos Molina, Fariba Mozafari, Renaud Mahieux, Masahiro Fujii, Nazli Azimi, Fatah Kashanchi

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Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax1 is a 40-kDa phosphoprotein, predominantly localized in the nucleus of the host cell, which functions to transactivate both viral and cellular promoters. It seems likely that HTLV-1, through expression of the viral regulatory protein Tax1, provides some initial alteration in cell metabolism predisposing the development of ATL. Here, we demonstrate that HTLV-1 infection in T-cell lines and patient samples causes overexpression of an early G1 cyclin, cyclin D2. The transcriptional up-regulation of the cyclin D2 gene is due to activation of Tax on the cyclin D2 gene. More important, we find that overexpression of cyclin D2 is accompanied by acquisition of new partners such as cyclin- dependent kinase 2 (cdk2), cdk4, and cdk6 in infected cells. This is in contrast to uninfected T cells, where cyclin D2 associates only with cdk6. Functional effects of these cyclin-cdk complexes in infected cells are shown by hyperphosphorylation of Rb and histone H1, indicators of active progression into S phase as well as changes in cellular chromatin and transcription machinery. These studies link HTLV-1 infection with changes of cellular cyclin gene expression, hence providing clues to development of T- cell leukemia.

Original languageEnglish
Pages (from-to)9917-9927
Number of pages11
JournalJournal of Virology
Volume73
Issue number12
StatePublished - 1 Dec 1999

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Deltaretrovirus
Cyclin D2
cyclin-dependent kinase
Cyclin-Dependent Kinases
cyclins
Up-Regulation
Adult T Cell Leukemia Lymphoma
Cyclins
T-lymphocytes
Genes
Virus Diseases
genes
leukemia
cells
Viral Regulatory and Accessory Proteins
Cyclin G1
Cyclin-Dependent Kinase 2
Tropical Spastic Paraparesis
T-Lymphocytes
T-Cell Leukemia

Cite this

Santiago, Francisco ; Clark, Elizabeth ; Chong, Siewyen ; Molina, Carlos ; Mozafari, Fariba ; Mahieux, Renaud ; Fujii, Masahiro ; Azimi, Nazli ; Kashanchi, Fatah. / Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1- infected cells. In: Journal of Virology. 1999 ; Vol. 73, No. 12. pp. 9917-9927.
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abstract = "Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax1 is a 40-kDa phosphoprotein, predominantly localized in the nucleus of the host cell, which functions to transactivate both viral and cellular promoters. It seems likely that HTLV-1, through expression of the viral regulatory protein Tax1, provides some initial alteration in cell metabolism predisposing the development of ATL. Here, we demonstrate that HTLV-1 infection in T-cell lines and patient samples causes overexpression of an early G1 cyclin, cyclin D2. The transcriptional up-regulation of the cyclin D2 gene is due to activation of Tax on the cyclin D2 gene. More important, we find that overexpression of cyclin D2 is accompanied by acquisition of new partners such as cyclin- dependent kinase 2 (cdk2), cdk4, and cdk6 in infected cells. This is in contrast to uninfected T cells, where cyclin D2 associates only with cdk6. Functional effects of these cyclin-cdk complexes in infected cells are shown by hyperphosphorylation of Rb and histone H1, indicators of active progression into S phase as well as changes in cellular chromatin and transcription machinery. These studies link HTLV-1 infection with changes of cellular cyclin gene expression, hence providing clues to development of T- cell leukemia.",
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Santiago, F, Clark, E, Chong, S, Molina, C, Mozafari, F, Mahieux, R, Fujii, M, Azimi, N & Kashanchi, F 1999, 'Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1- infected cells', Journal of Virology, vol. 73, no. 12, pp. 9917-9927.

Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1- infected cells. / Santiago, Francisco; Clark, Elizabeth; Chong, Siewyen; Molina, Carlos; Mozafari, Fariba; Mahieux, Renaud; Fujii, Masahiro; Azimi, Nazli; Kashanchi, Fatah.

In: Journal of Virology, Vol. 73, No. 12, 01.12.1999, p. 9917-9927.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1- infected cells

AU - Santiago, Francisco

AU - Clark, Elizabeth

AU - Chong, Siewyen

AU - Molina, Carlos

AU - Mozafari, Fariba

AU - Mahieux, Renaud

AU - Fujii, Masahiro

AU - Azimi, Nazli

AU - Kashanchi, Fatah

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N2 - Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax1 is a 40-kDa phosphoprotein, predominantly localized in the nucleus of the host cell, which functions to transactivate both viral and cellular promoters. It seems likely that HTLV-1, through expression of the viral regulatory protein Tax1, provides some initial alteration in cell metabolism predisposing the development of ATL. Here, we demonstrate that HTLV-1 infection in T-cell lines and patient samples causes overexpression of an early G1 cyclin, cyclin D2. The transcriptional up-regulation of the cyclin D2 gene is due to activation of Tax on the cyclin D2 gene. More important, we find that overexpression of cyclin D2 is accompanied by acquisition of new partners such as cyclin- dependent kinase 2 (cdk2), cdk4, and cdk6 in infected cells. This is in contrast to uninfected T cells, where cyclin D2 associates only with cdk6. Functional effects of these cyclin-cdk complexes in infected cells are shown by hyperphosphorylation of Rb and histone H1, indicators of active progression into S phase as well as changes in cellular chromatin and transcription machinery. These studies link HTLV-1 infection with changes of cellular cyclin gene expression, hence providing clues to development of T- cell leukemia.

AB - Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax1 is a 40-kDa phosphoprotein, predominantly localized in the nucleus of the host cell, which functions to transactivate both viral and cellular promoters. It seems likely that HTLV-1, through expression of the viral regulatory protein Tax1, provides some initial alteration in cell metabolism predisposing the development of ATL. Here, we demonstrate that HTLV-1 infection in T-cell lines and patient samples causes overexpression of an early G1 cyclin, cyclin D2. The transcriptional up-regulation of the cyclin D2 gene is due to activation of Tax on the cyclin D2 gene. More important, we find that overexpression of cyclin D2 is accompanied by acquisition of new partners such as cyclin- dependent kinase 2 (cdk2), cdk4, and cdk6 in infected cells. This is in contrast to uninfected T cells, where cyclin D2 associates only with cdk6. Functional effects of these cyclin-cdk complexes in infected cells are shown by hyperphosphorylation of Rb and histone H1, indicators of active progression into S phase as well as changes in cellular chromatin and transcription machinery. These studies link HTLV-1 infection with changes of cellular cyclin gene expression, hence providing clues to development of T- cell leukemia.

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