Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1

Abstract

A recently discovered potential tumor suppressor protein, Zac1, was previously shown to promote cell cycle arrest and apoptosis, and to act as a positive or negative transcriptional cofactor for nuclear receptors. Since these activities are common to Zac1 and p53, we tested for a functional interaction between these two proteins by investigating possible e ects of Zac1 on the transcriptional activator function of p53. Zac1 speci®cally enhanced the activity of p53-responsive promoters in cells expressing wild type p53. The same promoters were not activated by Zac1 in cells lacking functional p53, but the Zac1 e ect was restored by co-expression of p53. Zac1 bound to p53 and enhanced the activity of p53 or its N-terminal transcriptional activation domain fused to the DNA binding domain of Gal4. These results indicate that Zac1 served as a transcriptional coactivator for p53. The enhancement of p53 activity by Zac1 was much more dramatic in HeLa cells than in other cell lines tested. HeLa cells express human papillomavirus type 18 E6 protein which inactivates and causes the degradation of p53. Physical and functional interactions observed between Zac1 and E6 protein indicated that the dramatic activity of Zac1 in HeLa cells was due not only to Zac1's coactivator e ect on p53, but also to the ability of Zac1 to reverse E6 inhibition of p53. Oncogene (2001) 20, 2134 ± 2143.

A New Coactivator Function for Zac1's C2H2 Zinc Finger DNA-Binding Domain in Selectively Controlling PCAF Activity

“…Consistent with its putative role as a coactivator, Zac1 additionally associated with the ligand-binding domains of the androgen, estrogen, glucocorticoid, and thyroid hormone receptors and potently enhanced the transcriptional activities of these nuclear receptors. Also supporting the notion that Zac1 may have a broader role in coactivation, the protein was shown to increase the activity of the tumor suppressor p53 gene after binding to its activation domain (17).…”

“…In contrast to p53, Zac1 did not interact with the amino-terminal activation domain of p73 (Fig. 2D) (17), raising the possibility that Zac1 modulates the DNA-binding activity of p73. However, there was no evidence for an increase in p73 occupancy on the endogenous p21 Cip1 promoter in the presence of increasing amounts of Zac1 (see below; data not shown).…”

Zinc finger protein Zac1 is expressed in chondrogenic sites of the mouse

“…It also serves as a transcriptional coactivator by binding nuclear receptors and their coactivators, thereby playing both positive and negative roles in regulating nuclear receptor function (Huang and Stallcup, 2000). Furthermore, Zac1 binds to p53 and enhances p53-dependent gene activation (Huang et al, 2001).…”

Modulation of the Cyclin-Dependent Kinase Inhibitor p21WAF1/Cip1 Gene by Zac1 through the Antagonistic Regulators p53 and Histone Deacetylase 1 in HeLa Cells

“…Whether Zac1 acts as a NR coactivator or repressor depends on the type of NR, the cell line, or the reporter gene (15). Although Zac1 serves as a transcriptional coactivator for p53, it also acts as a transcriptional repressor for a viral oncoprotein, human papillomavirus E6.18, in HeLa cells (14). Thus, in order to determine the molecular mechanism by which Zac1 functions as a positive or negative regulator is important to accurately delineate the role that Zac1 plays within the gene networks that regulate cell proliferation, cell cycle arrest, and apoptosis.…”

“…Functionally, Zac1 not only exerts an antiproliferative effect but also acts as a transcriptional cofactor for p53 and a number of nuclear receptors (NR; refs. [13][14][15]. The NR coregulating activity of Zac1 may result from its ability to bind directly to NRs and to interact with two classes of NR coactivators: the p160 and the CBP/p300 family of coactivators.…”