SAPKs and transcription factors do the nucleocytoplasmic tango: Figure 1.

Agonists of retinoid X receptors (RXRs), which include the natural 9-cis-retinoic acid and synthetic analogs, are potent inducers of growth arrest and apoptosis in some cancer cells. As such, they are being used in clinical trials for the treatment and prevention of solid tumors and are used to treat cutaneous T cell lymphoma. However, the molecular mechanisms that underlie the anticancer effects of RXR agonists remain unclear. Here, we show that a novel pro-apoptotic pathway that is induced by RXR agonist is negatively regulated by casein kinase 1␣ (CK1␣). CK1␣ associates with RXR in an agonist-dependent manner and phosphorylates RXR. The ability of an RXR agonist to recruit CK1␣ to a complex with RXR in cells correlates inversely with its ability to inhibit growth. Remarkably, depletion of CK1␣ in resistant cells renders them susceptible to RXR agonist-induced growth inhibition and apoptosis. Our study shows that CK1␣ can promote cell survival by interfering with RXR agonist-induced apoptosis. Inhibition of CK1␣ may enhance the anti-cancer effects of RXR agonists.

Section: Ck1␣ Is Not Required For Transcriptional Activities Of Rxr Hmentioning

confidence: 99%

Casein Kinase 1α Interacts with Retinoid X Receptor and Interferes with Agonist-induced Apoptosis

Zhao¹,

Qin²,

Atangan³

et al. 2004

“…In the second pathway, the oxidized cysteine of Sty1 makes a direct disulfide linkage with a cysteine residue of Tpx1, the sole 2-Cys peroxiredoxin; this interaction is additionally required for full Sty1 activation (20). The active Sty1 then moves to the nucleus, and phosphorylates Atf1 therein (17), resulting in increased Atf1 stability and transcriptional activity (21). Activated Sty1 is also recruited to the chromosomes, in a manner dependent on Atf1 but independent of its phosphorylation status (22).…”

mentioning

confidence: 99%

“…Moreover, we show that Int6 stimulates the Sty1-dependent response by enhancing Atf1 expression in response to histidine starvation. The Sty1 MAPK (also known as Spc1 and Phh1) transduces the stress-activated signaling pathway in response to a number of conditions including oxidative stress, osmotic stress, and DNA damaging conditions (17,18). The mechanism of Sty1 activation is best studied in the H 2 O 2 -induced oxidative stress response, which involves two different pathways.…”

mentioning

confidence: 99%

Int6/eIF3e Promotes General Translation and Atf1 Abundance to Modulate Sty1 MAPK-dependent Stress Response in Fission Yeast

Udagawa

Nemoto

Wilkinson

et al. 2008

int-6 is one of the frequent integration sites for mouse mammary tumor viruses. Although its product is the e-subunit of translation initiation factor eIF3, other evidence indicates that it interacts with proteasomes or other proteins to regulate protein stability. Here we report that the fission yeast int6؉ is required for overcoming stress imposed by histidine starvation, using the drug 3-aminotriazole (3AT). Microarray and complementary Northern studies using wild-type, int6⌬ or gcn2⌬ mutants indicate that 3AT-treated wild-type yeast induces core environmental stress response (CESR) genes in addition to typical general amino acid control (GAAC) genes whose transcription depends on the eIF2 kinase, Gcn2. In agreement with this, Sty1 MAPK and its target transcription factor Atf1, which signal the CESR, are required for overcoming 3AT-induced starvation. We find that Int6 is required for maintaining the basal level of Atf1 and for rapid transcriptional activation of the CESR on 3AT-insult. Pulse labeling experiments indicate that int6⌬ significantly slows down de novo protein synthesis. Moreover, Atf1 protein half-life was reduced in int6⌬ cells. These effects would account for the compromised Atf1 activity on 3AT-induced stress. Thus, the robust protein synthesis promoted by intact eIF3 appears to be a part of the requisites for sound Sty1 MAPK-dependent signaling governed by the activity of the Atf1 transcription factor.Mouse mammary tumor virus integrates into the mouse genome, altering proteins or their expression and thereby eliciting mammary tumors. The sites of mouse mammary tumor virus integration were identified to delineate the molecular basis of the mammary tumorigenesis (see Refs. 1 and 2 for reviews). These so-called int sites include members of the Wnt (Wnt-1/int-1, Wnt-3, and Wnt-10b) and Fgf families (Fgf-3/ int-2, Fgf-4/hst, and Fgf-8/AIGF), Notch-4/int-3 and eIF3e/ int-6. Thus, all of the Int proteins except Int-6 are a well characterized growth factor or transmembrane receptor. Int-6 is an abundant protein and found to be identical to the e (p48)-subunit of eukaryotic translation initiation factor-3 (eIF3), 3 a multisubunit protein (of 11-13 subunits in mammals and plants) required for initiating protein synthesis (3). The eIF3 directly binds to the 40 S ribosomal subunit and mediates Met-tRNA i Met and mRNA binding to the ribosome (4). Int-6/eIF3e was recently determined to be a part of the functional core of mammalian eIF3, comprising only 6 subunits (5). Curiously, eIF3 isolated from the budding yeast Saccharomyces cerevisiae does not contain the homologue of Int-6/eIF3e (6, 7). Yet, eIF3 isolated from the fission yeast Schizosaccharomyces pombe includes its homologue Int6 (also known as Yin6) (8, 9). In addition to its role in translation, human Int-6 appears to regulate protein stability by directly binding to HIF2␣ (10) and MCM7 (11). In fission yeast, Int6 interacts with the 26 S proteasome to promote ubiquitin-dependent degradation of cyclin/Cdc13 and securin/Cut2 (12). However, the me...

“…ATF/CREB family proteins are among the conserved effector molecules that are regulated by the stress-activated MAP kinase (MAPK) cascade. In fission yeast, Atf1 and Pcr1, members of ATF/CREB family, are phosphorylated by the stress-activated Wis1 (MAPK kinase) and Sty1/Spc1 (MAPK) protein kinases, and this phosphorylation induces transcriptional activation of target genes (23)(24)(25)(26)(27). Moreover, many lines of evidence suggest potential roles for ATF/CREB family proteins in chromatin remodeling and gene silencing (28 -30).…”

mentioning

confidence: 99%

Regulation of Swi6/HP1-dependent Heterochromatin Assembly by Cooperation of Components of the Mitogen-activated Protein Kinase Pathway and a Histone Deacetylase Clr6

Kim

Choi

Shin

et al. 2004

102

119

A study of gene silencing within the mating-type region of fission yeast defines two distinct pathways responsible for the establishment of heterochromatin assembly. One is RNA interference-dependent and acts on centromere-homologous repeats (cenH). The other is a stochastic Swi6 (the fission yeast HP1 homolog)-dependent mechanism that is not fully understood. Here we find that activating transcription factor (Atf1) and Pcr1, the fission yeast bZIP transcription factors homologous to human ATF-2, are crucial for proper histone deacetylation of both H3 and H4. This deacetylation is a prerequisite for subsequent H3 lysine 9 methylation and Swi6-dependent heterochromatin assembly across the rest of the silent mating-type (mat) region lacking the RNA interference-dependent cenH repeat. Moreover, Atf1 and Pcr1 can form complexes with both a histone deacetylase, Clr6, and Swi6, and clr6 mutations affected the H3/H4 acetylation patterns, similar to the atf1 and pcr1 deletion mutant phenotypes at the endogenous mat loci and at the ctt1 ؉ promoter region surrounding ATF/CREbinding site. These data suggest that Atf1 and Pcr1 participate in an early step essential for heterochromatin assembly at the mat locus and silencing of transcriptional targets of Atf1. Furthermore, a phosphorylation event catalyzed by the conserved mitogen-activated protein kinase pathway is important for regulation of heterochromatin silencing by Atf1 and Pcr1. These findings suggest a role for the mitogen-activated protein kinase pathway and histone deacetylase in Swi6-based heterochromatin assembly.Methylation of histone H3 lysine 9 (H3 Lys-9) by the conserved H3 Lys-9-specific methyltransferase, Su(var)3-9 in flies, SUV39H1 in human, and Clr4 in the fission yeast Schizosaccharomyces pombe (1-4) correlates with heterochromatin assembly. The methylated Lys-9 residue recruits another conserved heterochromatin protein, which is called Swi6 in S. pombe and HP1 (heterochromatin protein 1) in higher eukaryotes (5, 6), leading to regional silencing of chromatin. In the fission yeast, recent studies (6 -8) addressing the silencing of the mating-type region provide insights for understanding the regulation of heterochromatin assembly in eukaryotes. Of particular interest, previous work (9) has defined sequential requirements for the establishment and maintenance of regional heterochromatic domains.Heterochromatin assembly at the mating-type region containing the mat2 and mat3 silent donor loci and an 11-kb interval (K region) between them requires several cis-acting DNA sequences as well as trans-acting factors (8, 10 -13). Heterochromatin formation at the centromeres and within the silent mat2/3 interval requires many of the same silencing factors, including Clr3 and Clr6 (H3/H4-specific histone deacetylases), the Clr4-Rik1 complexes, and Swi6 (2, 14 -19). The DNA elements involved in silencing within the entire 20 kb of the mat2/3 silent mating-type interval include REII (20), the mat3-M element including putative ATF 1 /CREB-binding sites (21), and the ...