Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain

Abstract

The proliferation rate of a cell population reflects a balance between cell division, cell cycle arrest, differentiation and apoptosis. The regulation of these processes is central to development and tissue homeostasis, whereas dysregulation may lead to overt pathological outcomes, notably cancer and neurodegenerative disorders. We report here the cloning of a novel zinc finger protein which regulates apoptosis and cell cycle arrest and was accordingly named Zac1. In vitro Zac1 inhibited proliferation of tumor cells, as evidenced by measuring colony formation, growth rate and cloning in soft agar. In vivo Zac1 abrogated tumor formation in nude mice. The antiproliferative activity of Zac1 was due to induction of extensive apoptosis and of G1 arrest, which proceeded independently of retinoblastoma protein and of regulation of p21(WAF1/Cip1), p27Kip1, p57Kip2 and p16INK4a expression. Zac1-mediated apoptosis was unrelated to cell cycle phase and G1 arrest was independent of apoptosis, indicating separate control of apoptosis and cell cycle arrest. Zac1 is thus the first gene besides p53 which concurrently induces apoptosis and cell cycle arrest.

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

“…The transient expression of Zac1 in different organs may be related to its role in cell proliferation and apoptosis (Spengler et al, 1997), but the biological significance of its expression in different organs remains to be explored. Our studies show that Zac1 is prominently and persistently expressed in all chondrogenic tissues, including sites of mesenchymal condensation before overt chondrogenesis and cartilaginous structures such as the vertebral body and limb cartilage.…”

“…Zac1, also known as Lot1 (lost on transformation) or Plagl1, is a recently characterized transcription factor containing seven zinc fingers of the C 2 H 2 type at the N-terminus (Spengler et al, 1997;Abdollahi et al, 1997a). The gene encoding Zac1 is located on human and mouse chromosomal regions that are maternally imprinted (Piras et al, 2000;Kamiya et al, 2000;Smith et al, 2002).…”

“…The gene encoding Zac1 is located on human and mouse chromosomal regions that are maternally imprinted (Piras et al, 2000;Kamiya et al, 2000;Smith et al, 2002). Zac1 inhibits tumor cell proliferation both in vitro and in vivo as a result of its induction of apoptosis and G1 cell cycle arrest (Spengler et al, 1997). Expression of Zac1 is frequently lost in tumor cell lines and down-regulated in primary tumors (Abdollahi et al, 1997b;Bilanges et al, 1999;Pagotto et al, 1999Pagotto et al, , 2000.…”

“…In adult mice, Zac1 expression was shown to be highest in the anterior pituitary gland, at lower levels in various areas of the brain, and very weak in other tissues (Spengler et al, 1997). During mouse embryonic and postnatal development, Zac1 was shown to have strong expression in brain areas with active proliferation, such as the ventricular zone, the external granular layer of the cerebellum, and numerous neuroepithelia (Valente and Auladell, 2001).…”

IRF-3-dependent and augmented target genes during viral infection

“…Two of the IRF-3-dependent genes are known transcription factors that stimulate apoptosis or growth suppression, Zac1 and Egr2/Knox-20. 38,39 In addition, there is an increase in expression of the Fas death domain-associated protein, Daax and a decrease in cyclin A1. Conversely, there is an apparent counterbalance to the promotion of apoptosis with the altered expression of genes that stimulate cellular proliferation.…”