RESEARCH - Reduced p53 in cells from patients with RA is associated with loss of radiation-induced apoptosis.

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Arthritis Rheum. 2005 Apr;52(4):1047-57.

Reduced p53 in peripheral blood mononuclear cells from patients with

rheumatoid arthritis is associated with loss of radiation-induced apoptosis.

Maas K, Westfall M, Pietenpol J, Olsen NJ, Aune T.

Vanderbilt University, Nashville, Tennessee.

OBJECTIVE: Patients with autoimmune disorders exhibit highly reproducible

gene expression profiles in their peripheral blood mononuclear cells. This

profile includes, at least in part, a collection of underexpressed genes

that encode proteins that inhibit cell cycle progression and stimulate

apoptosis. We aimed to determine whether this gene expression profile

confers functional liability on lymphocytes from patients with rheumatoid

arthritis (RA). METHODS: Viability studies in response to a panel of

proapoptotic stimuli revealed that T lymphocytes from patients with RA were

resistant to gamma radiation-induced apoptosis, a process known to be

dependent on p53. To assess p53 function in RA peripheral blood mononuclear

cells, baseline levels of p53 protein and TP53 transcript were measured in

patients with RA and controls. The cellular p53 response to gamma radiation

was also assessed by immunoblotting. RESULTS: Lymphocytes from patients with

RA had lower baseline levels of TP53 messenger RNA (mRNA) and p53 protein

than did those from control subjects and were deficient in their ability to

increase p53 after exposure to gamma radiation. A subgroup of patients with

RA had a second biochemical defect characterized by expression of very low

baseline levels of checkpoint kinase 2 mRNA and protein.

CONCLUSION: We conclude that defects in the expression of TP53 mRNA and, in

a subgroup, defects in expression of CHK2 mRNA, lead to severe defects in

apoptosis in patients with RA. We hypothesize that this liability may

contribute to autoimmunity.

PMID: 15818671

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

5818671 & dopt=Abstract

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