The gene PC3^TIS21/BTG2, prototype member of the PC3/BTG/TOB family: Regulator in control of cell growth, differentiation, and DNA repair?

Abstract

PC3 TIS21/BTG2 is the founding member of a family of genes endowed with antiproliferative properties, namely BTG1, ANA/BTG3, PC3B, TOB, and TOB2. PC3 was originally isolated as a gene induced by nerve growth factor during neuronal differentiation of rat PC12 cells, or by TPA in NIH3T3 cells (named TIS21), and is a marker for neuronal birth in vivo. This and other ®ndings suggested its implication in the process of neurogenesis as mediator of the growth arrest before differentiation. Remarkably, its human homolog, named BTG2, was shown to be p53-inducible, in conditions of genotoxic damage. PC3 TIS21/BTG2 impairs G 1 ±S progression, either by a Rb-dependent pathway through inhibition of cyclin D1 transcription, or in a Rb-independent fashion by cyclin E downregulation. PC3 TIS21/BTG2 might also control the G 2 checkpoint. Furthermore, PC3 TIS21/BTG2 interacts with carbon catabolite repressor protein-associated factor 1 (CAF-1), a molecule that associates to the yeast transcriptional complex CCR4 and might in¯uence cell cycle, with the transcription factor Hoxb9, and with the proteinarginine methyltransferase 1, that might control transcription through histone methylation. Current evidence suggests a physiological role of PC3 TIS21/BTG2 in the control of cell cycle arrest following DNA damage and other types of cellular stress, or before differentiation of the neuron and other cell types. The molecular function of PC3 TIS21/BTG2 is still unknown, but its ability to modulate cyclin D1 transcription, or to synergize with the transcription factor Hoxb9, suggests that it behaves as a transcriptional co-regulator.

Generation of Functional Dopamine Neurons from Neural Precursor Cells Isolated from the Subventricular Zone and White Matter of the Adult Rat Brain Using Nurr1 Overexpression

“…2). We further examine the expressions of RhoA (neurite extension [43]) and PC3 (neuronal birth [44]), resulting in no clear differences of their expression levels between the adult and embryonic NP cells. Expression of SCG10, enriched in the growth cones of the developing neurons [45], was rather decreased in the SVZ and WM cultures compared with that of E14 NP cells.…”

Btg1 and Btg2 gene expression during early chick development

“…It has been suggested that Btg proteins exert cellular functions by interacting with transcriptional coactivators or corepressors, hence modulating their transcriptional activities (Matsuda et al, 2001;Tirone, 2001;Duriez et al, 2004;Lim, 2006). For example, it has been found that Btg2 impairs G1-S cell cyclephase progression by inhibiting cyclin D1 transcription (Guardavaccaro et al, 2000), that it can associate with HoxB9 (Prevot et al, 2000), and BMPregulated Smad1 and 8 (Park et al, 2004) to promote their transcriptional activity, and that it can enhance Math1 promoter activity (Canzoniere et al, 2004).…”

“…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). 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).…”

“…In spite of having similar N-terminal sequences and activities, BTG proteins are smaller than Tob proteins and both groups are generally considered as subfamilies (Matsuda et al, 2001;Tirone, 2001;Jia and Meng, 2007). The Btg2 gene was the first member to be identified, as an immediate response gene in mouse and rat, in two different cellular contexts.…”

“…Overexpression of Btg/Tob members in different cellular models have assigned them antriproliferative and/or pro-differentiative functions (reviewed in (Tirone, 2001;Duriez et al, 2004). Btg1 has been shown to modulate avian myoblast differentiation in vitro (Marchal et al, 1995;Rodier et al, 1999), and Btg2 can promote differentiation and survival of cultured-neural cells (Corrente et al, 2002;el-Ghissassi et al, 2002).…”