Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human T cell leukemia virus type 1

Micol Silic-Benussi, Ilaria Cavallari, Tatiana Zorzan, Elisabetta Rossi, Hajime Hiraragi, Antonio Rosato, Kyoji Horie, Daniela Saggioro, Michael D. Lairmore, Luc Willems, Luigi Chieco-Bianchi, Donna M. D'Agostino, Vincenzo Ciminale

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Human T cell leukemia virus type 1 encodes an "accessory" protein named p13II that is targeted to mitochondria and triggers a rapid flux of K+ and Ca2+ across the inner membrane. In this study, we investigated the effects of p13II on tumorigenicity in vivo and on cell growth in vitro. Results showed that p13II significantly reduced the incidence and growth rate of tumors arising from c-myc and Ha-ras-cotransfected rat embryo fibroblasts. Consistent with these findings, HeLa-derived cell lines stably expressing p13II exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro. Mixed culture assays revealed that the phenotype of the p13II cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13II cell lines exhibited an enhanced response to Ca2+-mediated stimuli, as measured by increased sensitivity to C2-ceramide-induced apoptosis and by cAMP-responsive element-binding protein (CREB) phosphorylation in response to histamine. p13II-expressing Jurkat T cells also exhibited reduced proliferation, suggesting that the protein might exert similar effects in T cells, the primary target of HTLV-1 infection. These findings provide clues into the function of p13II as a negative regulator of cell growth and underscore a link between mitochondria, Ca2+ signaling, and tumorigenicity.

Original languageEnglish
Pages (from-to)6629-6634
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number17
DOIs
Publication statusPublished - Apr 27 2004

Fingerprint

Deltaretrovirus
Mitochondrial Proteins
Cell Proliferation
Cell Line
Mitochondria
Deltaretrovirus Infections
Growth
T-Lymphocytes
Neoplasms
Human T-lymphotropic virus 1
Jurkat Cells
HeLa Cells
Histamine
Carrier Proteins
Proteins
Embryonic Structures
Fibroblasts
Hot Temperature
Phosphorylation
Apoptosis

Keywords

  • Apoptosis
  • Calcium signaling
  • Retrovirus
  • Tumorigenicity

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human T cell leukemia virus type 1. / Silic-Benussi, Micol; Cavallari, Ilaria; Zorzan, Tatiana; Rossi, Elisabetta; Hiraragi, Hajime; Rosato, Antonio; Horie, Kyoji; Saggioro, Daniela; Lairmore, Michael D.; Willems, Luc; Chieco-Bianchi, Luigi; D'Agostino, Donna M.; Ciminale, Vincenzo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 17, 27.04.2004, p. 6629-6634.

Research output: Contribution to journalArticle

Silic-Benussi, Micol ; Cavallari, Ilaria ; Zorzan, Tatiana ; Rossi, Elisabetta ; Hiraragi, Hajime ; Rosato, Antonio ; Horie, Kyoji ; Saggioro, Daniela ; Lairmore, Michael D. ; Willems, Luc ; Chieco-Bianchi, Luigi ; D'Agostino, Donna M. ; Ciminale, Vincenzo. / Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human T cell leukemia virus type 1. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 17. pp. 6629-6634.
@article{235fd003638b4a7392a23f8a136b8221,
title = "Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human T cell leukemia virus type 1",
abstract = "Human T cell leukemia virus type 1 encodes an {"}accessory{"} protein named p13II that is targeted to mitochondria and triggers a rapid flux of K+ and Ca2+ across the inner membrane. In this study, we investigated the effects of p13II on tumorigenicity in vivo and on cell growth in vitro. Results showed that p13II significantly reduced the incidence and growth rate of tumors arising from c-myc and Ha-ras-cotransfected rat embryo fibroblasts. Consistent with these findings, HeLa-derived cell lines stably expressing p13II exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro. Mixed culture assays revealed that the phenotype of the p13II cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13II cell lines exhibited an enhanced response to Ca2+-mediated stimuli, as measured by increased sensitivity to C2-ceramide-induced apoptosis and by cAMP-responsive element-binding protein (CREB) phosphorylation in response to histamine. p13II-expressing Jurkat T cells also exhibited reduced proliferation, suggesting that the protein might exert similar effects in T cells, the primary target of HTLV-1 infection. These findings provide clues into the function of p13II as a negative regulator of cell growth and underscore a link between mitochondria, Ca2+ signaling, and tumorigenicity.",
keywords = "Apoptosis, Calcium signaling, Retrovirus, Tumorigenicity",
author = "Micol Silic-Benussi and Ilaria Cavallari and Tatiana Zorzan and Elisabetta Rossi and Hajime Hiraragi and Antonio Rosato and Kyoji Horie and Daniela Saggioro and Lairmore, {Michael D.} and Luc Willems and Luigi Chieco-Bianchi and D'Agostino, {Donna M.} and Vincenzo Ciminale",
year = "2004",
month = "4",
day = "27",
doi = "10.1073/pnas.0305502101",
language = "English",
volume = "101",
pages = "6629--6634",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "17",

}

TY - JOUR

T1 - Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human T cell leukemia virus type 1

AU - Silic-Benussi, Micol

AU - Cavallari, Ilaria

AU - Zorzan, Tatiana

AU - Rossi, Elisabetta

AU - Hiraragi, Hajime

AU - Rosato, Antonio

AU - Horie, Kyoji

AU - Saggioro, Daniela

AU - Lairmore, Michael D.

AU - Willems, Luc

AU - Chieco-Bianchi, Luigi

AU - D'Agostino, Donna M.

AU - Ciminale, Vincenzo

PY - 2004/4/27

Y1 - 2004/4/27

N2 - Human T cell leukemia virus type 1 encodes an "accessory" protein named p13II that is targeted to mitochondria and triggers a rapid flux of K+ and Ca2+ across the inner membrane. In this study, we investigated the effects of p13II on tumorigenicity in vivo and on cell growth in vitro. Results showed that p13II significantly reduced the incidence and growth rate of tumors arising from c-myc and Ha-ras-cotransfected rat embryo fibroblasts. Consistent with these findings, HeLa-derived cell lines stably expressing p13II exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro. Mixed culture assays revealed that the phenotype of the p13II cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13II cell lines exhibited an enhanced response to Ca2+-mediated stimuli, as measured by increased sensitivity to C2-ceramide-induced apoptosis and by cAMP-responsive element-binding protein (CREB) phosphorylation in response to histamine. p13II-expressing Jurkat T cells also exhibited reduced proliferation, suggesting that the protein might exert similar effects in T cells, the primary target of HTLV-1 infection. These findings provide clues into the function of p13II as a negative regulator of cell growth and underscore a link between mitochondria, Ca2+ signaling, and tumorigenicity.

AB - Human T cell leukemia virus type 1 encodes an "accessory" protein named p13II that is targeted to mitochondria and triggers a rapid flux of K+ and Ca2+ across the inner membrane. In this study, we investigated the effects of p13II on tumorigenicity in vivo and on cell growth in vitro. Results showed that p13II significantly reduced the incidence and growth rate of tumors arising from c-myc and Ha-ras-cotransfected rat embryo fibroblasts. Consistent with these findings, HeLa-derived cell lines stably expressing p13II exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro. Mixed culture assays revealed that the phenotype of the p13II cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13II cell lines exhibited an enhanced response to Ca2+-mediated stimuli, as measured by increased sensitivity to C2-ceramide-induced apoptosis and by cAMP-responsive element-binding protein (CREB) phosphorylation in response to histamine. p13II-expressing Jurkat T cells also exhibited reduced proliferation, suggesting that the protein might exert similar effects in T cells, the primary target of HTLV-1 infection. These findings provide clues into the function of p13II as a negative regulator of cell growth and underscore a link between mitochondria, Ca2+ signaling, and tumorigenicity.

KW - Apoptosis

KW - Calcium signaling

KW - Retrovirus

KW - Tumorigenicity

UR - http://www.scopus.com/inward/record.url?scp=2342462205&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2342462205&partnerID=8YFLogxK

U2 - 10.1073/pnas.0305502101

DO - 10.1073/pnas.0305502101

M3 - Article

C2 - 15100416

AN - SCOPUS:2342462205

VL - 101

SP - 6629

EP - 6634

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 17

ER -