Phosphorylation‐dependent binding of human transcription factor MOK2 to lamin A/C

Abstract

The zinc-finger transcription factor MOK2 recognizes both DNA and RNA through its zinc-finger motifs [1]. This dual affinity suggests that MOK2 may play a role in transcription, as well as in the post-transcriptional regulation of specific genes. We have shown that MOK2 represses expression of the interphotoreceptor retinoid-binding protein (IRBP) gene [2]. IRBP contains two MOK2-binding elements, a complete 18-bp MOK2-binding site, located in intron 2, and the essential 8-bp core MOK2-binding site (corresponding to the conserved 3¢-half site) which is in the IRBP promoter. MOK2 can bind to the 8-bp sequence in the IRBP promoter and repress transcription from this promoter. In the IRBP promoter, the TAAAGGCT MOK2-binding site overlaps with the photoreceptorspecific Crx-binding element, suggesting that MOK2 represses transcription by competing with the cone-rod homeobox protein for DNA binding and decreasing transcriptional activation by the cone-rod homeobox protein. The particular arrangement of the two MOK2-binding sites, observed in the human IRBP gene and also in a second human potential MOK2 target gene, Pax3, suggests that MOK2 may repress transcription via a dual mechanism. Previously, we identified lamin A ⁄ C proteins as binding partners for hsMOK2 in a yeast two-hybrid screen [3]. A-type lamins have been shown to bind hsMOK2 in vitro and in vivo through the coil 2 domain common to lamin A and lamin C, whereas the lamin A ⁄ C-binding site in hsMOK2 has been mapped to its N-terminal acidic domain. Divergent evolution has been observed between human and mouse MOK2 genes which results in the loss of this NH 2 -domain in the mouse gene [4]. An in silico search of MOK2 genes in different species has shown that the lamin-binding site is present only in primate MOK2 proteins. Furthermore, we have found that a fraction of human hsMOK2 protein is associated with the nuclear matrix. We therefore suggested that hsMOK2 interactions with lamin A ⁄ C and the nuclear matrix might be important for its

Diverse lamin-dependent mechanisms interact to control chromatin dynamics

“…This has been shown for SREBP1, Sp1, and Oct-1, which interact with prelamin A 56 - 58 and for pRb, Mok2, and cFos, which bind mature lamin A or lamin C 59 , 60 . Also lamin B1 is able to recruit the transcription factor Oct-1 to the nuclear envelope 61 , 62 .…”

Post-translational modifications of intermediate filament proteins: mechanisms and functions

“…Associations between cytoplasmic IFs and other proteins are regulated by O-linked glycosylation (GlcNAc) and phosphorylation, whereas lamin interactions with the nuclear membrane are regulated by farnesylation. Phosphorylation also regulates the interaction of lamins with lamin associated proteins, including transcription factors and other lamin-binding partners 168,169 . Lysine acetylation, phosphorylation and ubiquitination regulate IF filament formation, disassembly, and turnover in response to physiological and pathophysiologic cellular changes.…”

Nuclear Lamins

“…For example, the association of Oct-1 with lamin B1 at the nuclear envelope appears to be important for the oxidative stress response in MEFs, as lamin B1 deficiency leads to a dysregulation of Oct-1-dependent genes and to an increase in reactive oxygen species (Malhas et al 2009). Lamins A/C also interact with the transcription factors c-Fos, MOK2, and sterol response element binding protein 1 (SREBP1) (Dreuillet et al 2002;Lloyd et al 2002;Ivorra et al 2006;Dreuillet et al 2008;Harper et al 2009). In the case of c-Fos, its interaction with lamins A/C at the nuclear envelope appear to suppress AP-1 (activating protein 1) binding to DNA and transcriptional activity in an extracellular signal-regulated kinase (ERK) 1/2 activity-dependent fashion (Ivorra et al 2006;Gonzalez et al 2008).…”