Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-κB pathways

Eric J. Thompson, Kandavel Shanmugam, Christine L. Hattrup, Kari L. Kotlarczyk, Albert Gutierrez, Judy M. Bradley, Pinku Mukherjee, Sandra J Gendler

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Much of the ability of the MUC1 oncoprotein to foster tumorigenesis and tumor progression likely originates from the interaction of its cytoplasmic tail with proteins involved in oncogenic signaling. Many of these interactions are regulated by phosphorylation, as the cytoplasmic tail contains seven highly conserved tyrosines and several serine/threonine phosphorylation sites. We have developed a cell line-based model system to study the effects of tyrosine phosphorylation on MUC1 signaling, with particular emphasis on its effects on gene transcription. COS-7 cells, which lack endogenous MUC1, were stably infected with wild-type MUC1 or a MUC1 construct lacking all seven tyrosines (MUC1 Y0) and analyzed for effects on transcription mediated by the extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) pathways. COS.MUC1 Y0 cells showed heightened active ERK1/2 with increased activator protein-1 (AP-1) and signal transducer and activator of transcription 3 (STAT3) transcriptional activity; there was also a simultaneous decrease in NF-κB transcriptional activity and nuclear localization. These changes altered the phenotype of COS.MUC1 Y0 cells, as this line displayed increased invasion and enhanced [3H]thymidine incorporation. Analysis of the three lines also showed significant differences in their cell cycle profile and bromodeoxyuridine incorporation when the cells were serum starved. These data support the growing evidence that MUC1 is involved in transcriptional regulation and link MUC1 for the first time to the NF-κB pathway.

Original languageEnglish (US)
Pages (from-to)489-497
Number of pages9
JournalMolecular Cancer Research
Volume4
Issue number7
DOIs
StatePublished - Jul 2006

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Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Tyrosine
Phosphorylation
Cell Line
STAT3 Transcription Factor
COS Cells
Oncogene Proteins
Transcription Factor AP-1
Bromodeoxyuridine
Threonine
Thymidine
Serine
Cell Cycle
Carcinogenesis
Phenotype
Serum
Genes
Neoplasms
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-κB pathways. / Thompson, Eric J.; Shanmugam, Kandavel; Hattrup, Christine L.; Kotlarczyk, Kari L.; Gutierrez, Albert; Bradley, Judy M.; Mukherjee, Pinku; Gendler, Sandra J.

In: Molecular Cancer Research, Vol. 4, No. 7, 07.2006, p. 489-497.

Research output: Contribution to journalArticle

Thompson, Eric J. ; Shanmugam, Kandavel ; Hattrup, Christine L. ; Kotlarczyk, Kari L. ; Gutierrez, Albert ; Bradley, Judy M. ; Mukherjee, Pinku ; Gendler, Sandra J. / Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-κB pathways. In: Molecular Cancer Research. 2006 ; Vol. 4, No. 7. pp. 489-497.
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