title: Dwarfism and dysregulated proliferation in mice overexpressing the MYC antagonist MAD1.
abstract: The four members of the MAD family are bHLHZip proteins that heterodimerize with MAX and act as transcriptional repressors. The switch from MYC-MAX complexes to MAD-MAX complexes has been postulated to couple cell-cycle arrest with differentiation. The ectopic expression of Mad1 in transgenic mice led to early postnatal lethality and dwarfism and had a profound inhibitory effect on the proliferation of the hematopoietic cells and embryonic fibroblasts derived from these animals. Compared to wild-type cells, Mad1 transgenic fibroblasts arrested with altered morphology and reduced density at confluence, cycled more slowly, and were delayed in their progression from G0 to the S phase. These changes were accompanied by accumulation of hypophosphorylated retinoblastoma protein and p130. Cyclin D1-associated kinase activity was dramatically reduced in MAD1-overexpressing fibroblasts. However, wild-type cell-cycle distribution and morphology could be rescued in the Mad1 transgenic cells by the introduction of HPV-E7, but not an E7 mutant incapable of binding to pocket proteins. This indicates that the activities of the retinoblastoma family members, via the cyclin D pathway, are likely to be the major targets for MAD1-mediated inhibition of proliferation in primary mouse fibroblasts.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. christophe.queva@astra-zeneca.com
authors.forename: C
authors.initials: C
authors.lastname: Quéva
authors.forename: G A
authors.initials: GA
authors.lastname: McArthur
authors.forename: L S
authors.initials: LS
authors.lastname: Ramos
authors.forename: R N
authors.initials: RN
authors.lastname: Eisenman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002455:Cell Division; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004392:Dwarfism; D020964:Embryo Loss / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D015870:Gene Expression; D018257:Helix-Loop-Helix Motifs; D006412:Hematopoietic Stem Cells / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D010641:Phenotype; D012097:Repressor Proteins; D051785:Smad Proteins; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C499479:Mad protein, mouse; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D051785:Smad Proteins; D015534:Trans-Activators; C059731:oncogene protein E7, Human papillomavirus type 16; D018844:Cyclin-Dependent Kinases