Miz1 Is Required for Early Embryonic Development during Gastrulation

Abstract

Miz1 is a member of the POZ domain/zinc finger transcription factor family. In vivo, Miz1 forms a complex with the Myc oncoprotein and recruits Myc to core promoter elements. The MYC (or c-MYC) gene and two of its relatives, MYCL and MYCN, are causally involved in the genesis of a wide variety of human tumors (32). c-MYC encodes a transcription factor (Myc) that can both activate and repress transcription. Myc activates transcription as part of a heterodimeric complex with the Max protein (1, 23). The complex binds to specific sequences, termed E-boxes, and recruits both the Gcn5 and Tip60 histone acetylase complexes to E-box elements through interaction with the TRRAP protein (8,16,17,25,26). In addition, TRRAP-independent mechanisms of transcriptional activation have been demonstrated (30). These may involve interactions of Myc with the P-TEFb complex, which regulates transcriptional elongation (14). Both directed searches and a number of array analyses have identified a large number of genes that are activated by Myc in vivo (9,27,31,45).Similarly, a large number of genes have been identified that are repressed upon activation of Myc. However, the mechanisms of transcriptional repression by Myc have remained more elusive. For a number of genes, repression of Myc has been mapped to the core promoter, suggesting that Myc affects proteins that regulate transcription at or close to the start site of transcription (24). One suggestion has been that Myc directs the synthesis of a transcriptional repressor protein and thereby indirectly represses transcription, but such a repressor has not yet been identified. A second suggestion has been that MycMax complexes directly bind to the start site of one repressed gene, p27kip1 (49), but direct binding of Myc-Max complexes to start sites of other repressed genes has not been found. A third suggestion, therefore, has been that Myc is recruited to core promoters through protein-protein interactions with other transcription factors. A number of candidate interaction partners have been identified, including TFII-I (35), YY-1 (38), Smad2 (15), Sp1 (18), and Miz1 (34).Recently, evidence has accumulated that three genes, p15Ink4b (37, 40), p21Cip1 (20,36,43,48), and Mad4 (22), are repressed by Myc through interaction with Miz1. Miz1 is a transcription factor with 13 zinc fingers and a POZ/BTB domain at its amino terminus (4). Free Miz1 binds to the core promoter of all three genes and activates transcription. Upon binding to Myc, transcriptional activation by Miz1 is abolished, and the Myc-Miz1 complex acts as a transcriptional repressor; this is in part due to competition between p300 and Myc for binding to Miz1 (40). Array analyses and chromatin immunoprecipitation (ChIp) experiments suggest that several other genes that are repressed by Myc, including p57Kip2 (12) and C/EBP␣ (24), are directly repressed by Myc through interaction with Miz1 (V. Beuger and M. Eilers, unpublished observations).These findings suggest that interaction with Miz1 plays a central role in transcriptio...

ARF antagonizes the ability of Miz-1 to inhibit p53-mediated transactivation

“…Controversially, Adhikary et al (2003) reported that Miz-1 is required for early embryonic development during gastrulation. Similarly, Ziegelbauer et al (2004) reported that the loss of Miz-1 by RNA interference caused cells to accumulate in G1 and led to inhibition of cell proliferation in HepG2 cells.…”

Myc increases self-renewal in neural progenitor cells through Miz-1

“…Myc represses the cell cycle inhibitors p21Cip1, p15Ink4b and p57Kip2 via binding to Miz-1 (Adhikary et al, 2003;Seoane et al, 2002;Staller et al, 2001). A recent paper by Fasano et al reveals that Bmi-1 induced inhibition of the p21Cip1 is essential for neural stem cell self-renewal during development (Fasano et al, 2007).…”

The Role of MIZ-1 in MYC-Dependent Tumorigenesis

“…The murine miz-1 gene is essential during early development; homozygous deletion of miz-1 causes massive apoptosis of ectodermal cells at E7.5 during gastrulation (Adhikary et al 2003). The phenotype of miz-1 DPOZ mice is less severe, but mice still die late in embryogenesis .…”

“…In vivo, MIZ-1 is critical for suppression of CDKN1A in response to the tumor promoter TPA, during skin carcinogenesis (see below), and for repression of CDKN1A in response to endogenous DNA damage during recombination of T-cell receptors. Similarly, the CDKN1C ( p57Kip2) gene is a direct target of MIZ-1 and MYC represses CDKN1C in a MIZ-1-dependent manner during lymphomagenesis (Adhikary et al 2003;van Riggelen et al 2010).…”