A novel IL-6 response element confers specificity for JunB induction in M1 myeloid versus HepG2 hepatoma cells.

Format:

Book

Thesis/Dissertation

Author/Creator:

Tjin Tham Sjin, Robert Mark.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Molecular biology.

0307.

Local Subjects:

0307.

Physical Description:

154 pages

Contained In:

Dissertation Abstracts International 59-07B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Interleukin-6 (IL-6) is a multifunctional cytokine which plays an important role in a wide range of biological activities, including differentiation of murine M1 myeloid leukemic cells into mature macrophages. At the onset of M1 differentiation, a set of myeloid differentiation primary response (MyD) genes are induced, including the proto-oncogene JunB. However, the molecular nature of the mechanisms by which IL-6 activates the immediate early expression of MyD genes has not been elucidated. Towards this end, we used JunB as a paradigm to examine the IL-6-mediated activation of MyD genes, by identifying and characterizing IL-6 responsive cis-regulatory elements of the JunB promoter and transacting factors that bind to them.

It is shown that a novel IL-6 responsive element resides between sequences $-$65bp and $-$52bp upstream from the JunB transcription start site. This $-$65/-52 IL-6 response element (IL-6RE), which contains a CCAAT box motif, is shown to be necessary and sufficient for the IL-6 response. The STAT3 and CRE-like binding sites of the JunB promoter, identified as IL-6 responsiveness elements in HepG2 liver cells, play no role in JunB inducibility by IL-6 in M1 myeloid cells. Conversely, the $-$65/$-$52 IL-6RE is shown not to be necessary for JunB inducibility by IL-6 in liver cells. Thus, immediate early activation of JunB via the $-$65/$-$52 IL-6RE appears to be myeloid specific.

Analysis of nuclear proteins that bind to the $-$65/$-$52 IL-6RE revealed that NF-Y was a component of the protein complex bound to the $-$65/$-$52 IL-6RE. This is the first incident where NF-Y has been identified as a target for IL-6 signaling. In addition, the promoter regions of other MyD genes were found to contain NF-Y binding sites, suggesting that NF-Y plays a role in the mechanisms that lead to the coordinate induction by IL-6 of immediate early MyD genes following induction of myeloid differentiation.

Notes:

Source: Dissertation Abstracts International, Volume: 59-07, Section: B, page: 3256.

Supervisors: Dan Liebermann; Barbara Hoffman.

Thesis (Ph.D.)--University of Pennsylvania, 1998.

Local Notes:

School code: 0175.

ISBN:

9780591941302

Access Restriction:

Restricted for use by site license.