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J Biol Chem. 2001 Jan 26;276(4):2565-70. Epub 2000 Nov 7.

Functional disruption of the CD28 gene transcriptional initiator in senescent T cells.

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  • 1Departments of Medicine and Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. vallejo.abbe@mayo.edu

Abstract

We recently reported that aging is accompanied by the emergence of CD4(+)CD28(null) T cells, a functionally aberrant lymphocyte subset rarely seen in individuals younger than 40 years. Here, we directly examined whether the lack of CD28 expression is due to a defect at the level of transcriptional initiation. Molecular studies reveal that CD28 gene transcription is controlled by two sequence motifs, sites alpha and beta. In vitro transcription assays using initiator-dependent DNA templates revealed that reversed polarity or the deletion of either motif inhibited transcription, indicating that alpha/beta sequences constitute a composite initiator. Moreover, nuclear extracts from CD28(null) cells failed to activate transcription of alphabeta-initiator DNA templates. Transcription of such templates was, however, restored with the addition of extracts from CD28(+) cells. Although previously described initiator elements have been defined by a consensus sequence, the alphabeta-initiator has no homology to such sequence. These studies demonstrate that initiators have functions other than positioning elements for the basal transcription complex. Rather, initiators can have a direct role in regulating the expression of specific genes. The gain or loss of initiator activity can be an important determinant of cell phenotypes.

PMID:
11069899
[PubMed - indexed for MEDLINE]
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