Inhibition of Cell Proliferation by the Mad1 Transcriptional Repressor

Abstract

Mad1 is a basic helix-loop-helix-leucine zipper protein that is induced upon differentiation of a number

Proteasome inhibitor induced gene expression profiles reveal overexpression of transcriptional regulators ATF3, GADD153 and MAD1

“…The third transcription regulator analysed in this context, Mad1, was induced with very much delayed kinetics. Mad1 is a basic helix ± loop ± helix-leucine zipper (bHLH-Zip) transcriptional repressor protein that is induced upon cell di erentiation and inhibits proliferation by blocking cell cycle progression at G1 transition as shown in 3T3 cells (Roussel et al, 1996). Mad1 dimerizes with Max and binds to the same DNA sequences as Myc : Max dimers do, but antagonizes Myc (Ayer et al, 1993).…”

The basic region/helix – loop – helix/leucine zipper domain of Myc proto-oncoproteins: Function and regulation

“…This is based on the ®ndings that Mad proteins, as far as analysed, are expressed predominantly in resting or di erentiating cells which is in contrast to Myc proteins Zervos et al, 1993;Larsson et al, 1994;Hurlin et al, 1995b;Larsson et al, 1997;Queva et al, 1998). In addition Mad proteins inhibit cell growth and interfere with the transforming function of Myc (Lahoz et al, 1994;Cerni et al, 1995;Chen et al, 1995;Hurlin et al, 1995aHurlin et al, , 1997Koskinen et al, 1995;VaÈ strik et al, 1995;Roussel et al, 1996). Thus the Myc/Max/Mad network is composed of proteins that both positively and negatively a ect di erent aspects of cellular growth and it is thought that this network plays a pivotal role as molecular switch between proliferation, di erentiation, quiescence, and apoptosis.…”

Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes

“…Transgenic animals, in which c-myc is expressed under the control of an IgHenhancer, display a distinct preneoplastic phenotype which is characterized by an enhanced rate of proliferation and an increase in the number of preB cells (Langdon et al, 1986). Ectopic expression of Mad-1 protein blocks CSF-1 induced mitogenesis, demonstrating an essential role for Myc proteins in G1 progression (Roussel et al, 1996); this is supported by experiments using antisense oligonucleotides to inhibit expression of Myc (Heikkila et al, 1987;Prochownik et al, 1988). Also, knock-out animals in which the c-myc gene has been disrupted, die early in embryogenesis (Davis et al, 1993).…”