Mxi1-0, an alternatively transcribed Mxi1 isoform, is overexpressed in glioblastomas.
The c-Myc transcription factor regulates expression of genes related to cell growth, division, and apoptosis. Mxi1, a member of the Mad family, represses transcription of c-Myc-regulated genes by mediating chromatin condensation via histone deacetylase and the Sin3 corepressor. Mxi1 is a c-Myc antagonist and suppresses cell proliferation in vitro. Here, we describe the identification of Mxi1-0, a novel Mxi1 isoform that is alternatively transcribed from an upstream exon. Mxi1-0 and Mxi1 have different amino-terminal sequences, but share identical Max- and DNA-binding domains. Both isoforms are able to bind Max, to recognize E-box binding sites, and to interact with Sin3. Despite these similarities and in contrast to Mxi1, Mxi1-0 is predominantly localized to the cytoplasm and fails to repress c-Myc-dependent transcription. Although Mxi1-0 and Mxi1 are coexpressed in both human and mouse cells, the relative levels of Mxi1-0 are higher in primary glioblastoma tumors than in normal brain tissue. This variation in the levels of Mxi1-0 and Mxi1 suggests that Mxi1-0 may modulate the Myc-inhibitory activity of Mxi1. The identification of Mxi1-0 as an alternatively transcribed Mxi1 isoform has significant implications for the interpretation of previous Mxi1 studies, particularly those related to the phenotype of the mxi1 knockout mouse.
Engstrom
Lars D
LD
Section of Pediatric Hematology-Oncology, Department of Pediatrics and Communicable Diseases, The University of Michigan School of Medicine, Ann Arbor, MI 48109-0936, USA.
Youkilis
Andrew S
AS
Gorelick
Judith L
JL
Zheng
Datong
D
Ackley
Valerie
V
Petroff
Christy A
CA
Benson
Linda Q
LQ
Coon
Melissa R
MR
Zhu
Xiaoxiang
X
Hanash
Samir M
SM
Wechsler
Daniel S
DS
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D019556:COS Cells; D002522:Chlorocebus aethiops; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D003593:Cytoplasm / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C499330:MAX protein, human; C079440:MXI1 protein, human; C512788:Mxi1 protein, mouse; C067850:Myc associated factor X; C068422:Max protein, mouse