AbstractPC3TIS21/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 findings 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. PC3TIS21/BTG2 impairs G1–S progression, either by a Rb‐dependent pathway through inhibition of cyclin D1 transcription, or in a Rb‐independent fashion by cyclin E downregulation. PC3TIS21/BTG2 might also control the G2 checkpoint. Furthermore, PC3TIS21/BTG2 interacts with carbon catabolite repressor protein‐associated factor 1 (CAF‐1), a molecule that associates to the yeast transcriptional complex CCR4 and might influence cell cycle, with the transcription factor Hoxb9, and with the protein‐arginine methyltransferase 1, that might control transcription through histone methylation. Current evidence suggests a physiological role of PC3TIS21/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 PC3TIS21/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. © 2001 Wiley‐Liss, Inc.