Transcriptional regulation of MHC class I genes in adenovirus transformed cells: COUP-TF and NF-kappaB. A tale of two transcription factors.

Format:

Book

Thesis/Dissertation

Author/Creator:

Hou, Shihe.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Biochemistry.

Molecular biology.

0307.

0487.

Local Subjects:

0307.

0487.

Physical Description:

199 pages

Contained In:

Dissertation Abstracts International 63-11B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

The surface levels of MHC class I antigens are diminished on tumorigenic adenovirus 12 (Ad12-) transformed cells, enabling them to escape from immunosurveillant cytotoxic T lymphocytes (CTLs). This is due to the down-regulation of the class I transcriptional enhancer in which there is strong binding of repressor COUP-TFII and lack of binding of activator NF-kappaB. Even though NF-kappaB (p50/p65) translocates to the nuclei of Ad12-transformed cells, it fails to bind to DNA efficiently due to the hypophosphorylation of the p50 subunit.

In this study, we seek to elucidate the molecular mechanisms and dynamics of the class I transcriptional repression in tumorigenic Ad12-transformed cells. We demonstrated that COUP-TF represses transcription through its association with histone deacetylase. It was further shown that inhibition of histone deacetylases relieves the repression of MHC class I expression in Ad12-transformed cells.

On the other hand, in Ad12-transformed cells, NF-kappaB fails to bind to DNA due to hypophosphorylation of the p50 subunit. In this study, we identified the potential phospho-residues in p50 subunit critical for NF-kappaB binding through mutation analyses. Three serine residues, S65, S337 and S342 of human p50 protein were shown to be essential for DNA binding. In particular, serine 337 was further shown to be phosphorylated both in vitro and in vivo. This study shows for the first time that phosphorylation of at least one serine residue of p50 is essential for NF-kappaB DNA binding.

Finally, although TNF-alpha and IL-1beta were shown in this study to promote NF-kappaB DNA binding in Ad12-transformed cells, they fail to substantially activate class I transcription unless transcriptional repression by COUP-TFII was blocked. The results suggest that Ad12 likely employs a "fail-safe" mechanism to ensure that the transcription of class I genes remains tightly repressed under varying physiological conditions, thus providing tumorigenic Ad12-transformed cells with a means of escaping CTL recognition and lysis.

Notes:

Source: Dissertation Abstracts International, Volume: 63-11, Section: B, page: 5220.

Supervisor: Robert P. Ricciardi.

Thesis (Ph.D.)--University of Pennsylvania, 2002.

Local Notes:

School code: 0175.

ISBN:

9780493929040

Access Restriction:

Restricted for use by site license.