Cloning of the mouse BTG3 gene and definition of a new gene family (the BTG family) involved in the negative control of the cell cycle

Abstract

It is well known that loss of tumor suppressor genes and more generally of antiproliferative genes plays a key role in the development of most tumors. We report here the cloning of the mouse BTG3 gene and show that its human counterpart maps on chromosome 21. This evolutionarily conserved gene codes for a 30 kDa protein and is expressed in most adult murine and human tissues analyzed. However, we demonstrate that its expression is cell cycle dependent and peaks at the end of the G1 phase. This gene is homologous to the human BTG1, BTG2 and TOB genes which were demonstrated to act as inhibitors of cell proliferation. Its description allowed us to define better this seven gene family (the BTG gene family) at the structural level and to speculate about its physiological role in normal and tumoral cells. This family is mainly characterized by the presence of two conserved domains (BTG boxes A and B) of as yet undetermined function which are separated by a non-conserved 20-25 amino acid sequence.

BTG2TIS21/PC3 induces neuronal differentiation and prevents apoptosis of terminally differentiated PC12 cells

“…The human BTG2 TIS21/PC3 gene is a member of a newly identified family of six independent antiproliferative genes, namely, BTG1, ANA/BTG3, PC3B, TOB, TOB2 (Rouault et al, 1992;Matsuda et al, 1996;Guehenneux et al, 1997;Yoshida et al, 1998;Ikematsu et al, 1999;Buanne et al, 2000;Tirone, 2001). Although the biological functions of the BTG2 TIS21/PC3 protein remain to be elucidated, several studies have attempted to identify the different cues capable of inducing its expression.…”

Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome

“…There can be several consequences of the altered gene expression in WS. BTG3 overexpression (Figure 6a) is involved in the negative control of cell cycle progression from the G0/ G1 to S phase (Guehenneux et al, 1997). Thus, WS cells may progress through the cell cycle in spite of persisting DNA damage.…”

Btg1 and Btg2 gene expression during early chick development

“…Btg/ Tob genes are a newly characterized family of cell cycle modulators (Guehenneux et al, 1997). Studies in different model systems suggest that they act as antiproliferative genes, they can promote cell differentiation and also regulate apoptosis and cellular senescence (Matsuda et al, 2001;Tirone, 2001;Duriez et al, 2004;Lim, 2006).…”

“…Studies in different model systems suggest that they act as antiproliferative genes, they can promote cell differentiation and also regulate apoptosis and cellular senescence (Matsuda et al, 2001;Tirone, 2001;Duriez et al, 2004;Lim, 2006). Btg/Tob genes encode for a group of structurally related proteins, characterized by the presence of two novel and highly conserved domains ("antiproliferative" boxes A and B) located in the first 120 residues of the protein (Guehenneux et al, 1997;Guardavaccaro et al, 2000). This gene family is conserved across phylogeny, with two members identified in invertebrates: the gene Fog-3 in C. elegans (Chen et al, 2000) and the mRNA with accession number AF177464 in D. melanogaster.…”

“…Also, a structurally related gene has been characterized in amphioxus, the AmphiTOB gene (Holland et al, 1997). In vertebrates, the whole family is composed of at least six members that have been named differently in different species: Btg1, Btg2 (Tis21 in mouse and PC3 in rat), Btg3 (also named ANA for Abundant in Neuroepithelium Area), Btg4 (PC3B), Tob (Tob1), and Tob2 (Bradbury et al, 1991;Fletcher et al, 1991;Matsuda et al, 1996;Rouault et al, 1996;Guehenneux et al, 1997;Yoshida et al, 1998;Ikematsu et al, 1999). It has been proposed to name the family as APRO (AntiPROliferative) (Matsuda et al, 2001), but most studies and genetic databases continue using the BTG/Tob nomenclature, which will be adopted in this report.…”