Differential effects by Mad and Max on transformation by cellular and viral oncoproteins.
c-Myc is an essential component of the regulatory mechanisms controlling cell growth. Max is the obligatory partner of c-Myc for all its biological functions analysed to date. Recently two Max interacting proteins, Mad and Mxi1, have been identified. It has been suggested that these two proteins modulate c-Myc function, in the simplest model by competing with c-Myc for the interaction with Max. We have analysed different aspects of Mad function in comparison to Max. Native Mad/Max heterodimers bound specifically to a c-Myc/Max consensus DNA binding site. Furthermore Mad inhibited efficiently c-Myc, mutant p53, adenovirus E1a, or human papilloma virus type 16 transformation of rat embryo cells in cooperation with activated Ha-Ras. Myc transformed clones showed an increased cell cycle time and a reduced immortalization frequency after cotransfection with either mad or max. In contrast to Mad, Max did not inhibit E1a/Ha-Ras cotransformation but repressed c-Myc/Ha-Ras transformation efficiently. Mad delta N, an N-terminal deletion mutant of Mad, was as efficient in repressing c-Myc/Ha-Ras cotransformation as full length Mad but showed little inhibitory activity when assayed on E1a/Ha-Ras. Unlike wt Mad, Mad delta N had little effect on cell growth. Our data suggest that Mad affects cell growth at least in part by a c-Myc independent mechanism.
Cerni
C
C
Institut für Tumorbiologie, Universität Wien, Austria.
Bousset
K
K
Seelos
C
C
Burkhardt
H
H
Henriksson
M
M
Lüscher
B
B
D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D002453:Cell Cycle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000502:physiology*; D015870:Gene Expression; D016259:Genes, myc; D011905:Genes, ras; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins; D013329:Structure-Activity Relationship; D014157:Transcription Factors; D014162:Transfection
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C079439:MXD1 protein, human; D046911:Macromolecular Substances; C067850:Myc associated factor X; D009838:Oligodeoxyribonucleotides; D009856:Oncogene Proteins, Viral; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D016283:Proto-Oncogene Proteins p21(ras)