The integrated-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3β and cAMP-responsive element-binding protein-dependent pathways

M. D'Amico, J. Hulit, D. F. Amanatullah, B. T. Zafonte, C. Albanese, B. Bouzahzah, M. Fu, Leonard H. Augenlicht, L. A. Donehower, K. I. Takemaru, R. T. Moon, R. Davis, M. P. Lisanti, M. Shtutman, J. Zhurinsky, A. Ben-Ze'ev, A. A. Troussard, S. Dedhar, R. G. Pestell

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the pRB tumor suppressor protein. Cyclin D1 is overexpressed in 20-30% of human breast tumors and is induced both by oncogenes including those for Ras, Neu, and Src, and by the β-catenin/lymphoid enhancer factor (LEF)/T cell factor (TCF) pathway. The ankyrin repeat containing serine-threonine protein kinase, integrin-linked kinase (ILK), binds to the cytoplasmic domain of β1 and β3 integrin subunits and promotes anchorage-independent growth. We show here that ILK overexpression elevates cyclin D1 protein levels and directly induces the cyclin D1 gene in mammary epithelial cells. ILK activation of the cyclin D1 promoter was abolished by point mutation of a cAMP-responsive element-binding protein (CREB)/ATF-2 binding site at nucleotide -54 in the cyclin D1 promoter, and by overexpression of either glycogen synthase kinase-3β (GSK-3β) or dominant negative mutants of CREB or ATF-2. Inhibition of the PI 3-kinase and AKT/protein kinase B, but not of the p38, ERK, or JNK signaling pathways, reduced ILK induction of cyclin D1 expression. ILK induced CREB transactivation and CREB binding to the cyclin D1 promoter CRE. Wnt-1 overexpression in mammary epithelial cells induced cyclin D1 mRNA and targeted overexpression of Wnt-1 in the mammary gland of transgenic mice increased both ILK activity and cyclin D1 levels. We conclude that the cyclin D1 gene is regulated by the Wnt-1 and ILK signaling pathways and that ILK induction of cyclin D1 involves the CREB signaling pathway in mammary epithelial cells.

Original languageEnglish (US)
Pages (from-to)32649-32657
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number42
StatePublished - Oct 20 2000

Fingerprint

bcl-1 Genes
Glycogen Synthase Kinase 3
Cyclin D1
Carrier Proteins
Phosphotransferases
Genes
TCF Transcription Factors
Breast
Epithelial Cells
Ankyrin Repeat
Tumor Suppressor Proteins
Catenins
Proto-Oncogene Proteins c-akt
Holoenzymes
integrin-linked kinase
MAP Kinase Signaling System
Protein-Serine-Threonine Kinases
Human Mammary Glands
Phosphatidylinositol 3-Kinases
Oncogenes

ASJC Scopus subject areas

  • Biochemistry

Cite this

D'Amico, M., Hulit, J., Amanatullah, D. F., Zafonte, B. T., Albanese, C., Bouzahzah, B., ... Pestell, R. G. (2000). The integrated-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3β and cAMP-responsive element-binding protein-dependent pathways. Journal of Biological Chemistry, 275(42), 32649-32657.

The integrated-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3β and cAMP-responsive element-binding protein-dependent pathways. / D'Amico, M.; Hulit, J.; Amanatullah, D. F.; Zafonte, B. T.; Albanese, C.; Bouzahzah, B.; Fu, M.; Augenlicht, Leonard H.; Donehower, L. A.; Takemaru, K. I.; Moon, R. T.; Davis, R.; Lisanti, M. P.; Shtutman, M.; Zhurinsky, J.; Ben-Ze'ev, A.; Troussard, A. A.; Dedhar, S.; Pestell, R. G.

In: Journal of Biological Chemistry, Vol. 275, No. 42, 20.10.2000, p. 32649-32657.

Research output: Contribution to journalArticle

D'Amico, M, Hulit, J, Amanatullah, DF, Zafonte, BT, Albanese, C, Bouzahzah, B, Fu, M, Augenlicht, LH, Donehower, LA, Takemaru, KI, Moon, RT, Davis, R, Lisanti, MP, Shtutman, M, Zhurinsky, J, Ben-Ze'ev, A, Troussard, AA, Dedhar, S & Pestell, RG 2000, 'The integrated-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3β and cAMP-responsive element-binding protein-dependent pathways', Journal of Biological Chemistry, vol. 275, no. 42, pp. 32649-32657.
D'Amico, M. ; Hulit, J. ; Amanatullah, D. F. ; Zafonte, B. T. ; Albanese, C. ; Bouzahzah, B. ; Fu, M. ; Augenlicht, Leonard H. ; Donehower, L. A. ; Takemaru, K. I. ; Moon, R. T. ; Davis, R. ; Lisanti, M. P. ; Shtutman, M. ; Zhurinsky, J. ; Ben-Ze'ev, A. ; Troussard, A. A. ; Dedhar, S. ; Pestell, R. G. / The integrated-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3β and cAMP-responsive element-binding protein-dependent pathways. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 42. pp. 32649-32657.
@article{048c904c175f4209b844dbbd4f1c18a7,
title = "The integrated-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3β and cAMP-responsive element-binding protein-dependent pathways",
abstract = "The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the pRB tumor suppressor protein. Cyclin D1 is overexpressed in 20-30{\%} of human breast tumors and is induced both by oncogenes including those for Ras, Neu, and Src, and by the β-catenin/lymphoid enhancer factor (LEF)/T cell factor (TCF) pathway. The ankyrin repeat containing serine-threonine protein kinase, integrin-linked kinase (ILK), binds to the cytoplasmic domain of β1 and β3 integrin subunits and promotes anchorage-independent growth. We show here that ILK overexpression elevates cyclin D1 protein levels and directly induces the cyclin D1 gene in mammary epithelial cells. ILK activation of the cyclin D1 promoter was abolished by point mutation of a cAMP-responsive element-binding protein (CREB)/ATF-2 binding site at nucleotide -54 in the cyclin D1 promoter, and by overexpression of either glycogen synthase kinase-3β (GSK-3β) or dominant negative mutants of CREB or ATF-2. Inhibition of the PI 3-kinase and AKT/protein kinase B, but not of the p38, ERK, or JNK signaling pathways, reduced ILK induction of cyclin D1 expression. ILK induced CREB transactivation and CREB binding to the cyclin D1 promoter CRE. Wnt-1 overexpression in mammary epithelial cells induced cyclin D1 mRNA and targeted overexpression of Wnt-1 in the mammary gland of transgenic mice increased both ILK activity and cyclin D1 levels. We conclude that the cyclin D1 gene is regulated by the Wnt-1 and ILK signaling pathways and that ILK induction of cyclin D1 involves the CREB signaling pathway in mammary epithelial cells.",
author = "M. D'Amico and J. Hulit and Amanatullah, {D. F.} and Zafonte, {B. T.} and C. Albanese and B. Bouzahzah and M. Fu and Augenlicht, {Leonard H.} and Donehower, {L. A.} and Takemaru, {K. I.} and Moon, {R. T.} and R. Davis and Lisanti, {M. P.} and M. Shtutman and J. Zhurinsky and A. Ben-Ze'ev and Troussard, {A. A.} and S. Dedhar and Pestell, {R. G.}",
year = "2000",
month = "10",
day = "20",
language = "English (US)",
volume = "275",
pages = "32649--32657",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "42",

}

TY - JOUR

T1 - The integrated-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3β and cAMP-responsive element-binding protein-dependent pathways

AU - D'Amico, M.

AU - Hulit, J.

AU - Amanatullah, D. F.

AU - Zafonte, B. T.

AU - Albanese, C.

AU - Bouzahzah, B.

AU - Fu, M.

AU - Augenlicht, Leonard H.

AU - Donehower, L. A.

AU - Takemaru, K. I.

AU - Moon, R. T.

AU - Davis, R.

AU - Lisanti, M. P.

AU - Shtutman, M.

AU - Zhurinsky, J.

AU - Ben-Ze'ev, A.

AU - Troussard, A. A.

AU - Dedhar, S.

AU - Pestell, R. G.

PY - 2000/10/20

Y1 - 2000/10/20

N2 - The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the pRB tumor suppressor protein. Cyclin D1 is overexpressed in 20-30% of human breast tumors and is induced both by oncogenes including those for Ras, Neu, and Src, and by the β-catenin/lymphoid enhancer factor (LEF)/T cell factor (TCF) pathway. The ankyrin repeat containing serine-threonine protein kinase, integrin-linked kinase (ILK), binds to the cytoplasmic domain of β1 and β3 integrin subunits and promotes anchorage-independent growth. We show here that ILK overexpression elevates cyclin D1 protein levels and directly induces the cyclin D1 gene in mammary epithelial cells. ILK activation of the cyclin D1 promoter was abolished by point mutation of a cAMP-responsive element-binding protein (CREB)/ATF-2 binding site at nucleotide -54 in the cyclin D1 promoter, and by overexpression of either glycogen synthase kinase-3β (GSK-3β) or dominant negative mutants of CREB or ATF-2. Inhibition of the PI 3-kinase and AKT/protein kinase B, but not of the p38, ERK, or JNK signaling pathways, reduced ILK induction of cyclin D1 expression. ILK induced CREB transactivation and CREB binding to the cyclin D1 promoter CRE. Wnt-1 overexpression in mammary epithelial cells induced cyclin D1 mRNA and targeted overexpression of Wnt-1 in the mammary gland of transgenic mice increased both ILK activity and cyclin D1 levels. We conclude that the cyclin D1 gene is regulated by the Wnt-1 and ILK signaling pathways and that ILK induction of cyclin D1 involves the CREB signaling pathway in mammary epithelial cells.

AB - The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the pRB tumor suppressor protein. Cyclin D1 is overexpressed in 20-30% of human breast tumors and is induced both by oncogenes including those for Ras, Neu, and Src, and by the β-catenin/lymphoid enhancer factor (LEF)/T cell factor (TCF) pathway. The ankyrin repeat containing serine-threonine protein kinase, integrin-linked kinase (ILK), binds to the cytoplasmic domain of β1 and β3 integrin subunits and promotes anchorage-independent growth. We show here that ILK overexpression elevates cyclin D1 protein levels and directly induces the cyclin D1 gene in mammary epithelial cells. ILK activation of the cyclin D1 promoter was abolished by point mutation of a cAMP-responsive element-binding protein (CREB)/ATF-2 binding site at nucleotide -54 in the cyclin D1 promoter, and by overexpression of either glycogen synthase kinase-3β (GSK-3β) or dominant negative mutants of CREB or ATF-2. Inhibition of the PI 3-kinase and AKT/protein kinase B, but not of the p38, ERK, or JNK signaling pathways, reduced ILK induction of cyclin D1 expression. ILK induced CREB transactivation and CREB binding to the cyclin D1 promoter CRE. Wnt-1 overexpression in mammary epithelial cells induced cyclin D1 mRNA and targeted overexpression of Wnt-1 in the mammary gland of transgenic mice increased both ILK activity and cyclin D1 levels. We conclude that the cyclin D1 gene is regulated by the Wnt-1 and ILK signaling pathways and that ILK induction of cyclin D1 involves the CREB signaling pathway in mammary epithelial cells.

UR - http://www.scopus.com/inward/record.url?scp=0034692686&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034692686&partnerID=8YFLogxK

M3 - Article

C2 - 10915780

AN - SCOPUS:0034692686

VL - 275

SP - 32649

EP - 32657

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 42

ER -