Brca1 required for T cell lineage development but not TCR loci rearrangement.
Brca1 (breast cancerl, early onset) deficiency results in early embryonic lethality. As Brca1 is highly expressed in the T cell lineage, a T cell-specific disruption of Brca1 was generated to assess the role of Brca1 in relation to T lymphocyte development. We found that thymocyte development in Brca1-/- mice was impaired not as a result of V(D)J T cell receptor (TCR) recombination but because thymocytes had increased expression of tumor protein p53. Chromosomal damage accumulation and abnormal cell death were observed in mutant cells. We found that cell death inhibitor Bcl-2 overexpression, or p53-/- backgrounds, completely restored survival and development of Brca1-/- thymocytes; peripheral T cell numbers were not totally restored in Brcal-/- p53-/- mice; and that a mutant background for p21 (cyclin-dependent kinase inhibitor 1A) did not restore Brca1-/- thymocyte development, but partially restored peripheral T cell development. Thus, the outcome of Brca1 deficiency was dependent on cellular context, with the major defects being increased apoptosis in thymocytes, and defective proliferation in peripheral T cells.
Mak
T W
TW
Amgen Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1.
Hakem
A
A
McPherson
J P
JP
Shehabeldin
A
A
Zablocki
E
E
Migon
E
E
Duncan
G S
GS
Bouchard
D
D
Wakeham
A
A
Cheung
A
A
Karaskova
J
J
Sarosi
I
I
Squire
J
J
Marth
J
J
Hakem
R
R
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D015329:Gene Rearrangement, T-Lymphocyte / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D019313:BRCA1 Protein