Dwarfism and dysregulated proliferation in mice overexpressing the MYC antagonist MAD1.
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.
Quéva
C
C
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. christophe.queva@astra-zeneca.com
McArthur
G A
GA
Ramos
L S
LS
Eisenman
R N
RN
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
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