Abstract/Details

Elevated JNK activation contributes to transformation and resistance to apoptosis in an in vitro model of transformation and in primary brain tumors


1999 1999

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Abstract (summary)

Mitogen activated protein kinases (MAPKs) are commonly utilized by many kinase pathways in response to stimulation by growth factors, cytokines, and environmental once activated, these kinases translocate from the cytoplasm to the nucleus stresses where they modify cellular responses by phosphorylating transcription factors. Employment of MAPKs has been shown to be essential for such diverse processes as cell growth, differentiation, and apoptosis. Of the three established mammalian MAPKs, the extracellular signal-regulated kinase (ERK) a the best characterized. Stimulation of ERK activity by mitogenic factors, such as epidermal growth factor (EGF), has been shown to be essential for cell cycle progression. c-Jun N-terminal kinase (JNK) is another member of the MAPK family. In contrast to ERK, JNK is poorly activated by growth factors, but potently upregulated by environmental stresses and cytokines. Sustained JNK activation has been shown to lead to the induction of apoptosis, implicating this MAIM as an anti oncogenic factor.

EGFRvIII is a naturally occurring variant of the EGF receptor that was originally identified in human brain tumors. When expressed in NIH3T3 fibroblasts, this constitutively active mutant receptor enhances proliferation and protects cells from apoptosis. Analysis of the ERK pathway in EGFRvIII expressing cells revealed that this MAP kinase was not activated, questioning the importance of the ERK pathway in promoting transformation. We investigated whether the JNK pathway was altered in EGFRvIII expressing cells and found a high, chronic level of JNK activation that was not observed in cells overexpressing the normal EGF receptor. Incubating cells expressing EGFRvIII with specific inhibitors of the EGF receptor or PI 3-kinase down-regulated JNK activity, suggesting that these kinases were upstream regulators of the JNK pathway. In addition, inhibiting JNK activation was associated with a loss of properties related to transformation, and the enhanced JNK activation did not promote apoptosis in these cells. These findings implicate constitutive JNK activation in transformation by EGFRvIII.

Given the ambiguity concerning the functional significance of the JNK pathway in cellular responses, we then decided to study the regulation and function of JNK in spontaneously occurring astrocytic neoplasms. Western blot analysis of primary brain tumors showed that 17 of 21 tumor samples had elevated JNK phosphorylation. Kinase assays revealed that 9 of 13 brain tumor lines activated JNK in response to EGF, whereas none of 5 normal cell fines analyzed, including astrocytes activated JNK to the some extent. Expression of JNKAPF, a kinase deficient form of JNK, inhibited basal and EGF mediated anchorage-independent growth and protection from cell death in two glial tumor cell lines. These findings suggest that the enhanced JNK activation seen in brain tumors contributes to anchorage-independent growth and cell survival.

Indexing (details)


Subject
Molecular biology;
Cellular biology
Classification
0307: Molecular biology
0379: Cellular biology
Identifier / keyword
Biological sciences; Apoptosis; Brain tumors; JNK activation; MAP kinases; Resistance
Title
Elevated JNK activation contributes to transformation and resistance to apoptosis in an in vitro model of transformation and in primary brain tumors
Author
Antonyak, Marc A.
Number of pages
107
Publication year
1999
Degree date
1999
School code
0272
Source
DAI-B 61/02, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780599678262, 0599678267
Advisor
Wong, Albert
University/institution
Thomas Jefferson University
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
9963594
ProQuest document ID
304544212
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304544212
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