Wild-type p53 activates SAP expression in lymphoid cells.
SAP is an adaptor molecule with one SH2 domain and it is expressed in activated T and NK cells, where it is required for the appropriate signaling from the SLAM family of surface receptors. Deleted or mutated SAP genes that encode functionally defective protein are associated with the X-linked lymphoproliferative disease (XLP). This primary immunodeficiency is characterized by extreme sensitivity to Epstein-Barr virus (EBV) infection, dysgammaglobulinemia and a high rate of lymphoma development. The vigorous T- and B-cell proliferation that follows EBV infection and the high incidence of lymphomas (30%) in XLP patients might reflect functional defects in cell cycle and/ or apoptosis control. Our experiments show that SAP is a target of p53. In Burkitt lymphoma (BL) lines transfected with a temperatur-sensitive (ts) p53, SAP mRNA and protein expression was dependent on wild-type (wt) p53. Activation of endogenous wt p53 in BLs and lymphoblastoid cell lines led to the induction of SAP and this was inhibited by the specific p53 inhibitor pifithrin-alpha. Cell lines that carried mutant p53 did not express SAP under similar conditions. Moreover, we have shown binding of wt p53 to the promoter region of SAP by ChIP assay. Our results suggest that SAP contributes to the execution of some p53 functions.
Nagy
N
N
Microbiology and Tumor Biology Center, Karolinska Institute, 171 77 Stockholm, Sweden. Noemi.Nagy@mtc.ki.se
Takahara
M
M
Nishikawa
J
J
Bourdon
J C
JC
Kis
L L
LL
Klein
G
G
Klein
E
E
D001483:Base Sequence; D002051:Burkitt Lymphoma; D045744:Cell Line, Tumor; D004249:DNA Damage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010835:Phytohemagglutinins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D013696:Temperature; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; D010835:Phytohemagglutinins; D012333:RNA, Messenger; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D016159:Tumor Suppressor Protein p53