Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-κB and tumor progression

Punita Dhawan, Amar B. Singh, Darrel L. Ellis, Ann Richmond

Research output: Contribution to journalArticle

219 Citations (Scopus)

Abstract

The serine/threonine kinase Akt/protein kinase B and the pleiotropic transcription factor nuclear factor-κB [NF-κB (p50/p65) play important roles in the control of cell proliferation, apoptosis, and oncogenesis. Previous studies from our laboratory have shown the constitutive activation of NF-κB in melanoma cells. However, the mechanism of this activation is not clearly understood. The purpose of this study was to explore the role of Akt in the activation of NF-κB during melanoma tumor progression. Based on our observation that two of the five melanoma cell lines examined exhibit constitutive Akt activation, we evaluated Akt activation by immunohistochemistry in a series of pigmented skin lesions using an antibody specific for phospho-Akt Ser-473. Normal and slightly dysplastic nevi exhibited no significant Akt expression, in marked contrast to the dramatic Akt immunoreactivity seen in severely dysplastic nevi and melanomas (66.3% positive). When these same lesions were stained for nuclear p65, a similar expression pattern was observed. In addition, interruption of Akt activation resulted in increased apoptosis and decreased NF-κB promoter activity. These results indicate that activation of Akt kinase is linked to enhanced NF-κB nuclear localization and transactivation. We propose that activation of Akt may be an early marker for tumor progression in melanoma.

Original languageEnglish (US)
Pages (from-to)7335-7342
Number of pages8
JournalCancer Research
Volume62
Issue number24
StatePublished - Dec 15 2002

Fingerprint

Proto-Oncogene Proteins c-akt
Melanoma
Up-Regulation
Dysplastic Nevus Syndrome
Neoplasms
Phospho-Specific Antibodies
Nevi and Melanomas
Apoptosis
Protein-Serine-Threonine Kinases
Tumor Biomarkers
Transcriptional Activation
Carcinogenesis
Transcription Factors
Phosphotransferases
Immunohistochemistry
Cell Proliferation
Cell Line
Skin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-κB and tumor progression. / Dhawan, Punita; Singh, Amar B.; Ellis, Darrel L.; Richmond, Ann.

In: Cancer Research, Vol. 62, No. 24, 15.12.2002, p. 7335-7342.

Research output: Contribution to journalArticle

@article{181bb328449d43a2bd09683b493f6247,
title = "Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-κB and tumor progression",
abstract = "The serine/threonine kinase Akt/protein kinase B and the pleiotropic transcription factor nuclear factor-κB [NF-κB (p50/p65) play important roles in the control of cell proliferation, apoptosis, and oncogenesis. Previous studies from our laboratory have shown the constitutive activation of NF-κB in melanoma cells. However, the mechanism of this activation is not clearly understood. The purpose of this study was to explore the role of Akt in the activation of NF-κB during melanoma tumor progression. Based on our observation that two of the five melanoma cell lines examined exhibit constitutive Akt activation, we evaluated Akt activation by immunohistochemistry in a series of pigmented skin lesions using an antibody specific for phospho-Akt Ser-473. Normal and slightly dysplastic nevi exhibited no significant Akt expression, in marked contrast to the dramatic Akt immunoreactivity seen in severely dysplastic nevi and melanomas (66.3{\%} positive). When these same lesions were stained for nuclear p65, a similar expression pattern was observed. In addition, interruption of Akt activation resulted in increased apoptosis and decreased NF-κB promoter activity. These results indicate that activation of Akt kinase is linked to enhanced NF-κB nuclear localization and transactivation. We propose that activation of Akt may be an early marker for tumor progression in melanoma.",
author = "Punita Dhawan and Singh, {Amar B.} and Ellis, {Darrel L.} and Ann Richmond",
year = "2002",
month = "12",
day = "15",
language = "English (US)",
volume = "62",
pages = "7335--7342",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "24",

}

TY - JOUR

T1 - Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-κB and tumor progression

AU - Dhawan, Punita

AU - Singh, Amar B.

AU - Ellis, Darrel L.

AU - Richmond, Ann

PY - 2002/12/15

Y1 - 2002/12/15

N2 - The serine/threonine kinase Akt/protein kinase B and the pleiotropic transcription factor nuclear factor-κB [NF-κB (p50/p65) play important roles in the control of cell proliferation, apoptosis, and oncogenesis. Previous studies from our laboratory have shown the constitutive activation of NF-κB in melanoma cells. However, the mechanism of this activation is not clearly understood. The purpose of this study was to explore the role of Akt in the activation of NF-κB during melanoma tumor progression. Based on our observation that two of the five melanoma cell lines examined exhibit constitutive Akt activation, we evaluated Akt activation by immunohistochemistry in a series of pigmented skin lesions using an antibody specific for phospho-Akt Ser-473. Normal and slightly dysplastic nevi exhibited no significant Akt expression, in marked contrast to the dramatic Akt immunoreactivity seen in severely dysplastic nevi and melanomas (66.3% positive). When these same lesions were stained for nuclear p65, a similar expression pattern was observed. In addition, interruption of Akt activation resulted in increased apoptosis and decreased NF-κB promoter activity. These results indicate that activation of Akt kinase is linked to enhanced NF-κB nuclear localization and transactivation. We propose that activation of Akt may be an early marker for tumor progression in melanoma.

AB - The serine/threonine kinase Akt/protein kinase B and the pleiotropic transcription factor nuclear factor-κB [NF-κB (p50/p65) play important roles in the control of cell proliferation, apoptosis, and oncogenesis. Previous studies from our laboratory have shown the constitutive activation of NF-κB in melanoma cells. However, the mechanism of this activation is not clearly understood. The purpose of this study was to explore the role of Akt in the activation of NF-κB during melanoma tumor progression. Based on our observation that two of the five melanoma cell lines examined exhibit constitutive Akt activation, we evaluated Akt activation by immunohistochemistry in a series of pigmented skin lesions using an antibody specific for phospho-Akt Ser-473. Normal and slightly dysplastic nevi exhibited no significant Akt expression, in marked contrast to the dramatic Akt immunoreactivity seen in severely dysplastic nevi and melanomas (66.3% positive). When these same lesions were stained for nuclear p65, a similar expression pattern was observed. In addition, interruption of Akt activation resulted in increased apoptosis and decreased NF-κB promoter activity. These results indicate that activation of Akt kinase is linked to enhanced NF-κB nuclear localization and transactivation. We propose that activation of Akt may be an early marker for tumor progression in melanoma.

UR - http://www.scopus.com/inward/record.url?scp=0037115394&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037115394&partnerID=8YFLogxK

M3 - Article

C2 - 12499277

AN - SCOPUS:0037115394

VL - 62

SP - 7335

EP - 7342

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 24

ER -