Engstrom Lars D, Youkilis Andrew S, Gorelick Judith L, Zheng Datong, Ackley Valerie, Petroff Christy A, Benson Linda Q, Coon Melissa R, Zhu Xiaoxiang, Hanash Samir M, Wechsler Daniel S
Section of Pediatric Hematology-Oncology, Department of Pediatrics and Communicable Diseases, The University of Michigan School of Medicine, Ann Arbor, MI 48109-0936, USA.
Neoplasia. 2004 Sep-Oct;6(5):660-73. doi: 10.1593/neo.04244.
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.
c-Myc转录因子调控与细胞生长、分裂及凋亡相关的基因表达。Mxi1是Mad家族的成员之一，它通过组蛋白去乙酰化酶和Sin3共抑制因子介导染色质浓缩，从而抑制c-Myc调控基因的转录。Mxi1是c-Myc的拮抗剂，在体外可抑制细胞增殖。在此，我们描述了Mxi1-0的鉴定，它是一种新的Mxi1异构体，由一个上游外显子选择性转录产生。Mxi1-0和Mxi1具有不同的氨基末端序列，但共享相同的Max结合域和DNA结合域。两种异构体都能够结合Max，识别E盒结合位点，并与Sin3相互作用。尽管有这些相似之处，但与Mxi1不同的是，Mxi1-0主要定位于细胞质，并且不能抑制c-Myc依赖的转录。虽然Mxi1-0和Mxi1在人和小鼠细胞中均有共表达，但在原发性胶质母细胞瘤肿瘤中，Mxi1-0的相对水平高于正常脑组织。Mxi1-0和Mxi1水平的这种差异表明，Mxi1-0可能会调节Mxi1对Myc的抑制活性。将Mxi1-0鉴定为选择性转录的Mxi1异构体，对解释先前的Mxi1研究具有重要意义，特别是那些与mxi1基因敲除小鼠表型相关的研究。
