Functional characterization of a novel BTB/POZ‐domain protein ZBTB8A

Human BTB/POZ proteins play important roles in the regulation of cell cycle, differentiation, and development. Some of the transcription factors with BTB/POZ domain (e.g., BCL6, FBI‐1, ZBTB2 and ZBTB5) have been characterized as oncogenic factor regulating expression of the genes of the p53 pathway which is important regulator in the cell cycle progression and proliferation. The ZBTB8A consists of 441 amino acids which contains a BTB/POZ domain at N‐terminus and two C2H2 type zinc fingers at C‐terminus. Immuno‐cytochemistry assay showed that the ZBTB8A detected in nucleus speckles. MTT assays and FACS analysis showed that ZBTB8A stimulates cell proliferation and cell cycle progression. ZBTB8A represses transcription of the genes of p53 pathway, which include ARF, Hdm2, p53 and p21. Most of all, ZBTB8A strongly represses p21 gene transcription. In particular, ZBTB8A repressed transcription of a p21 by binding competition with Sp1 at the proximal Sp1 binding elements. Also, ZBTB8A repress p21 by interfering with p53 binding to the distal p53 binding element of p21. Serial analysis of gene expression (SAGE) analysis showed that ZBTB8A is highly expressed in pancreatic cancer tissues. Overall our data suggested that ZBTB8A is a transcription repressor of p21, and ZBTB8A may be a novel proto‐oncogene stimulating cell proliferation.