The promyelocytic leukemia zinc finger protein down-regulates apoptosis and expression of the proapoptotic BID protein in lymphocytes

Abstract

The promyelocytic leukemia zinc finger (PLZF) gene, involved in rare cases of acute promyelocytic leukemia, encodes a Krü ppeltype zinc finger transcription factor. It has been reported that PLZF affects myeloid cell growth, differentiation, and apoptosis. However, the function of PLZF in the lymphoid compartment, where PLZF is also expressed, remains largely unknown. To investigate a potential relationship between PLZF expression in lymphocytes and programmed cell death, an inducible model of stable clones of the lymphoid Jurkat cell line was created by using the tet-off system. Although induction of PLZF expression by itself did not produce changes in the basal levels of apoptosis, PLZF had a significant anti-apoptotic effect in Jurkat cells cultured in conditions of serum starvation, as measured by annexin V staining and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. In addition, retarded loss of mitochondrial transmembrane potential was observed in the PLZF-expressing clones, suggesting that PLZF protects from cell death through a mitochondrial-dependent mechanism. To identify apoptosis-related targets of PLZF, a screen for differential expression identified BID, a proapoptotic member of the Bcl2 family, as significantly down-regulated by PLZF. Furthermore, a high-affinity PLZF-binding site element was identified upstream of the BID transcriptional start site, as assessed by electrophoretic mobility-shift assays. These results suggest that BID is a target of PLZF repression and a candidate gene to mediate the PLZF-induced resistance to apoptosis.

Role of Promyelocytic Leukemia Zinc Finger (PLZF) in Cell Proliferation and Cyclin-dependent Kinase Inhibitor 1A (p21WAF/CDKN1A) Gene Repression

“…Plzf knock-out mice showed increased expression of p21 and p53 in spermatogonia, suggesting that Plzf is important in maintaining proliferative spermatogonia. Also, PLZF was shown to down-regulate apoptosis by inhibiting expression of the proapoptotic BID protein in lymphocytes (26). In this article, we were able to show that PLZF expression is increased in some cancers, like clear cell renal cell carcinoma, glioblastoma, and seminoma.…”

“…The number of spermatogonia was decreased (12). PLZF was shown to down-regulate apoptosis by inhibiting expression of the proapoptotic BID protein in lymphocytes (26). These data suggest that PLZF might stimulate cell proliferation.…”

Deletion of a conserved noncoding sequence in Plzf intron leads to Plzf down‐regulation in limb bud and polydactyly in the rat

“…In addition to limb development and spermatogenesis, Plzf has been also implicated in apoptosis (Parrado et al, 2004), cell cycle regulation (Yeyati et al, 1999), tumorigenesis (Piazza et al, 2001;Felicetti et al, 2004), and hematopoiesis (Piazza et al, 2004;Labbaye et al, 2008). Its functional versatility has also been shown by identification of Plzf as a crucial member of distinct metabolic and signaling pathways controlling blood pressure (Schefe et al, 2006;Naray-Fejes-Toth et al, 2008), and angiotensin II-induced cardiac hypertrophy (Senbonmatsu et al, 2003).…”

A novel cervical cancer suppressor 3 (CCS‐3) interacts with the BTB domain of PLZF and inhibits the cell growth by inducing apoptosis

“…Promyelocytic leukemia zinc finger protein (PLZF) is a sequence-specific DNAbinding protein containing nine C-terminal C 2 H 2 zinc finger motifs and an N-terminal BTB (broad complex, tramtrack, bric-a-brac)/POZ (Pox virus and zinc finger) [1][2][3][4]. PLZF functions as a transcriptional regulator for cell cycle progression by binding to the promoter of target genes, such as those for cyclin A and the interleukin-3 receptor a subunit [5][6][7][8].…”