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Biochemistry. in the Article “The Med1 Subunit of the Yeast Mediator Complex Is Involved in Both Transcriptional Activation An 3330 Corrections Proc. Natl. Acad. Sci. USA 96 (1999) Biochemistry. In the article “The Med1 subunit of the yeast Neurobiology. In the article “Caspase-1 is activated in neural mediator complex is involved in both transcriptional activation cells and tissue with amyotrophic lateral sclerosis-associated and repression” by Darius Balciunas, Cecilia Ga¨lman,Hans mutations in copper-zinc superoxide dismutase” by Piera Ronne, and Stefan Bjo¨rklund, which appeared in number 2, Pasinelli, David R. Borchelt, Megan K. Houseweart, Don W. January 19, 1999, of Proc. Natl. Acad. Sci. USA (96, 376–381), Cleveland, and Robert H. Brown, Jr., which appeared in due to a printer’s error, the affiliation symbols were incorrect. number 26, December 22, 1998, of Proc. Natl. Acad. Sci. USA The correct author line, affiliation line, and address footnotes (95, 15763–15768), the following corrections should be noted. appear below. An erroneous version of Fig. 6 was published. The lane indicated as G41D represents lumbo-sacral spinal cord extract from G85R transgenic mice. In Fig. 7a, cell viability is ex- DARIUS BALCIUNAS*†,CECILIA GALMAN¨ ‡§, pressed as % of untreated cells and not as % of viability. HANS RONNE*†, AND STEFAN BJORKLUND¨ ‡¶ ‡Department of Medical Biochemistry and Biophysics, Umeå University, Physiology. In the article “Inositol 1,4,5-tris-phosphate acti- S-901 87 Umeå, Sweden; and *Department of Medical Biochemistry and vation of inositol tris-phosphate receptor Ca21 channel by Microbiology, Uppsala University Biomedical Center, Box 582, 751 23 21 Uppsala, Sweden ligand tuning of Ca inhibition” by Don-On Daniel Mak, Sean McBride, and J. Kevin Foskett, which appeared in number 26, December 22, 1998, of Proc. Natl. Acad. Sci. USA †Present address: Department of Plant Biology, Uppsala Genetic Center, Swedish University of Agricultural Sciences, Box 7080, (95, 15821–15825), due to printer’s errors, the following cor- S-75007 Uppsala, Sweden. rections should be noted. The title of the article should read §Present address: CNT, Karolinska Institute at NOVUM, 141 57 “Inositol 1,4,5-trisphosphate activation of inositol trisphos- Huddinge, Sweden. phate receptor Ca21 channel by ligand tuning of Ca21 inhibi- ¶To whom reprint requests should be addressed. e-mail: ste@ tion.” On page 15821, the first line of the abstract should read panther.cmb.umu.se. “Inositol 1,4,5-trisphosphate (IP3)” instead of “Inositol 1,4,5- tris-phosphate (IP3),” and on page 15821, in the right column, Medical Sciences. In the article “Activation of « protein kinase the first line of the abbreviations footnote should read “IP3, C correlates with a cardioprotective effect of regular ethanol inositol 1,4,5-trisphosphate” instead of “IP3, inositol 1,4,5-tris- consumption” by Masami Miyamae, Manuel M. Rodriguez, S. phosphate.” Albert Camacho, Ivan Diamond, Daira Mochly-Rosen, and Vincent M. Figueredo, which appeared in number 14, July 7, Physiology. In the article “Post-priming actions of ATP on 1998, of Proc. Natl. Acad. Sci. USA (95, 8262–8267), the Ca21-dependent exocytosis in pancreatic beta cells” by Noriko following correction should be noted. On page 8264, an Takahashi, Takashi Kadowaki, Yoshio Yazaki, Graham C. R. incorrect Fig. 1 was printed. The correct figure and its accom- Ellis-Davies, Yasushi Miyashita, and Haruo Kasai, which panying legend are reproduced below. appeared in number 2, January 19, 1999, of Proc. Natl. Acad. Sci. USA (96, 760–765), the following corrections should be noted. On page 761, left column, line 11 should read “2- nitrophenyl-EGTA” instead of “DMNPE-4.” Also, on page 765, left column, lines 11–15 should read “(ii) glucose in- 21 creased insulin exocytosis, even when [Ca ]i was clamped at a high level and KATP channels were open (9, 11). These observations can be explained readily by the ATP-sensing mechanism identified in the present study.” FIG. 1. LVDP prior to 45 min of global ischemia and during reperfusion in four groups of perfused guinea pig hearts (n 5 9 for each group): 1, following 8 wk 15% ethanol-derived calories (E); 2, pair-fed controls (‚); 3, following 8 wk of ethanol, before and after 10 mM chelerythrine (F); and 4, pair-fed controls, before and after chelerythrine (■). LVDP recovery is significantly greater in hearts from ethanol-treated animals (P , 0.05 at each 6-min interval). Chelerythrine abolished ethanol’s protective effect on LVDP recov- ery. Data are presented as mean 6 SEM (SEM not included for group 2 but lie well within SEM of groups 3 and 4). Downloaded by guest on September 27, 2021 Proc. Natl. Acad. Sci. USA Vol. 96, pp. 376–381, January 1999 Biochemistry The Med1 subunit of the yeast mediator complex is involved in both transcriptional activation and repression (cyclin CyRNA polymerase IIytranscription) DARIUS BALCIUNAS*, CECILIA GA¨LMAN†‡,HANS RONNE‡, AND STEFAN BJO¨RKLUND†§ †Department of Medical Biochemistry and Biophysics, Umeå University, S-901 87 Umeå, Sweden; and *Department of Medical Biochemistry and Microbiology, Uppsala University Biomedical Center, Box 582, 751 23 Uppsala, Sweden Communicated by Roger D. Kornberg, Stanford University School of Medicine, Stanford, CA, December 1, 1998 (received for review October 6, 1998) ABSTRACT The mediator complex is essential for regu- mediator then is released from the core polymerase and can lated transcription in vitro. In the yeast Saccharomyces cerevisiae, participate in another round of initiation (15). Srb11 and Srb10 mediator comprises >15 subunits and interacts with the C- is another cyclin-kinase complex that also phosphorylates the terminal domain of the largest subunit of RNA polymerase II, CTD, but this phosphorylation is thought to occur before binding thus forming an RNA polymerase II holoenzyme. Here we to the promoter, thus preventing initiation (16). describe the molecular cloning of the MED1 cDNA encoding the Several subunits of the yeast mediator complex originally were 70-kDa subunit of the mediator complex. Yeast cells lacking the identified by genetic screens for mutations that would relieve MED1 gene are viable but show a complex phenotype including transcriptional repression (17, 18). Thus, ssn (19) or gig (20) partial defects in both repression and induction of the GAL genes. mutations cause a partial relief of glucose repression, rox muta- Together with results on other mediator subunits, this implies tions (21) cause a relief of oxygen repression, and are mutations that the mediator is involved in both transcriptional activation (22) cause a relief of mating type repression. Subsequent work and repression. Similar to mutations in the SRB10 and SRB11 revealed that many of the corresponding genes are identical. For genes encoding cyclin C and the cyclin C-dependent kinase, a example, SRB10 is identical to SSN3, GIG2, and ARE1. It should disruption of the MED1 gene can partially suppress loss of the be emphasized that most of the corresponding mutations also Snf1 protein kinase. We further found that a lexA-Med1 fusion affect transcriptional activation. For example, GAL gene induc- protein is a strong activator in srb11 cells, which suggests a tion, which is reduced in med2 and med6ts cells, is also affected in functional link between Med1 and the Srb10y11 complex. Fi- srb10 cells (7, 12). Thus, it appears that mutations in these genes nally, we show that the Med2 protein is lost from the mediator may result in either loss of repression or loss of induction, on purification from Med1-deficient cells, indicating a physical depending on the circumstances. In this paper, we describe the interaction between Med1 and Med2. cloning of a cDNA encoding Med1, the 70-kDa subunit of the mediator complex, and functional analysis of the gene in yeast. There is mounting biochemical and genetic evidence identifying Our data show that Med1 is required for proper regulation of the mediator complex as a key factor in regulating RNA poly- transcription and is also important for the stability of the RNA merase II-dependent transcription. In vitro transcription per- polymerase II holoenzyme. formed with pure, 12-subunit core polymerase and essential general transcription factors does not respond to activator pro- MATERIALS AND METHODS teins, but addition of the mediator complex to this minimal system both stimulates basal transcription, enhances TFIIH-dependent Yeast Strains. Saccharomyces cerevisiae strain BJ926 was used phosphorylation of the polymerase C-terminal domain (CTD), to purify the RNA polymerase II holoenzyme for amino acid and enables transcriptional regulation (1–3). Mediator purified to sequence determination of Med1. All other experiments were homogeneity is a complex of .15 polypeptides, several of which performed in W303–1A congenic strains (23). The mig1, snf1, and are encoded by known genes, such as SRB2,-4,-5,-6, and -7, med2-D1::HIS3 disruptions have been described (7, 24, 25). The GAL11, SIN4, RGR1, and ROX3 (3–5). However, eight mediator med1-D2::HIS3 disruption was made by cloning the HIS3 BamHI polypeptides were not identified previously and were designated fragment between NsiI and XbaI sites in MED1. The Med1–8 according to their apparent molecular weight in SDSy med1-D2::LEU2 and med1-D2::URA3 disruptions have the LEU2 PAGE. Six of them, Pgd1 (Med3) and Med2, -4y5, -6, -7, and -8 HpaI-SalI fragment and the URA3 HindIII fragment, respec- recently were identified and cloned (6, 7). tively, cloned into the same position. The srb11-D1::LEU2 dis- Mediator binds to the CTD of the largest subunit of the RNA ruption was made by cloning the LEU2 HpaI-SalI fragment polymerase II, thus forming the holo-RNA polymerase II. A between the BsaBI and BglII sites of SRB11. The GAL1-lacZ similar higher molecular weight form of RNA polymerase II also reporter has an EcoRI-Sau3AI fragment of the GAL1 promoter was identified by Young and coworkers (8) in studies of the fused to an SphI-AgeI fragment of pLGD312 (26) containing the CTD-interacting proteins encoded by the suppressor of RNA CYC1-lacZ fusion.
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