Upregulation of apolipoprotein L6 and L1, two BH3-only pro-death proteins, by p53 in cancer cells Free

LB-38

We recently cloned and characterized two novel BH3-only pro-death proteins, apolipoprotein L6 (ApoL6) and ApoL1 and showed that ApoL6 induces mitochondria-mediated apoptosis (1), whereas the ApoL1 induces autophagic cell death in cancer cells. TP53, a well-characterized tumor suppressor and transactivating factor, plays a critical role in the suppression of tumorigenesis by the induction of programmed cell death. TP53 functioning as a sequence-specific DNA-binding protein appears to be central to its roles as a tumor suppressor. A number of BH3-only pro-death genes, such as PUMA, NOXA and BAX, are direct downstream targets of TP53 in TP53-induced cell death. In the current study, we investigated upregulation of ApoL6 and ApoL1 by TP53. Using Tet-Off, TP53 inducible DLD-1.p53 colorectal cancer cells (2), quantitative RT-PCR and immunoblotting analysis, we showed that both ApoL6 and L1 are significantly upregulated by TP53 in time-dependent manner; upregulation was observed as early as 4 hours after TP53 overexpression. In addition, using biocomputational method, we found that the promoter region of ApoL6 or L1 each harbors two TP53 transcriptional activation sites. Taken together, our results suggest that expression of ApoL1 and L6, two novel BH3-only pro-death genes, is upregulated by TP53 in TP53-induced cell death. (1). Z. Liu et al (2005) Apolipoprotein L6, a novel pro-apoptotic BH3-only protein, induces mitochondria-mediated apoptosis in cancer cells. Mol. Can. Res. 3, 21-31. (2). S. Gu et al (2004) Global investigation of p53-induced apoptosis through quantitative profiling regulatory proteins using comparative amino acid-coded tagging proteomics. Mol. Cell. Proteomics, 3, 998-1008.