Nuclear protein phosphorylation and growth control

Meek, DavidW .; Street, A. J.

doi:10.1042/bj2870001

Cited by 136 publications

(77 citation statements)

References 189 publications

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“…We also tested a one copy EMS- Finally, we also tested alanine substitutions at Ser-343/344 and at Ser-293 individually or in combination with the casein kinase II sites at Ser-347/348 ( Figure 6a, constructs G and H). In some cases phosphorylation in or near the basic region of other DNA binding proteins has been shown to inhibit their activity (Hunter and Karin, 1992;Meek and Street, 1992). However, we again did not observe signi®cant di erences in transactivation potential of the altered proteins compared to wildtype (Figure 6b, 6c and data not shown).…”

Section: E Ects Of Phosphorylation On Transactivationmentioning

confidence: 50%

“…Phosphorylation has been found to regulate the activities of many transcription factors and protooncogenes (Hunter and Karin, 1992;Meek and Street, 1992). Several studies have investigated the role of phosphorylation in c-Myc function, and most of these focused on the casein kinase II sites in the C-terminal domain (Luscher et al, 1989) or the Thr-58/Ser-62 sites in the N-terminus transactivation domain.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of c-Myc and cell immortalization alters c-Myc phosphorylation

Lutterbach

1997

Oncogene

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Using an extensive series of deletion and site-speci®c mutation constructs, we have identi®ed ®ve new phosphorylation sites in c-Myc in the N-terminal transactivation domain and near the C-terminal DNA binding/heterodimerization domain. We have also found that Thr-58 phosphorylation is regulated by speci®c cellular events. When c-Myc is overexpressed in cells Thr-58 phosphorylation was greatly enhanced in the overexpressed, exogenous c-Myc as compared with the endogenous protein. In contrast, an inhibition of Thr-58 phosphorylation and an enhancement of Serine 62 phosphorylation was observed in c-Myc from immortalized cells compared with primary cells. No signi®cant changes in c-Myc phosphorylation were found when transformed and nontransformed cells were compared. Finally, mutations at these phosphorylation sites, either individually or in combination with previously described sites, did not a ect the ability of c-Myc to transactivate through the CACGTG Myc/Max DNA binding sites. These results further suggest that either the molecular role for c-Myc phosphorylation does not involve modulating transcriptional activity of c-Myc or that the CACGTG site does not represent a physiological promoter element.

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Section: E Ects Of Phosphorylation On Transactivationmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Overexpression of c-Myc and cell immortalization alters c-Myc phosphorylation

Lutterbach

1997

Oncogene

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“…In vivo wild-type and mutant p53 is multiply phosphorylated at its carboxy terminal domain (Bischo et al, 1990;StuÈ rzbecher et al, 1990;Meek and Street, 1992). In addition, p53 was found to be associated with protein kinases p34 cdc2 (Bischo et al, 1990;StuÈ rzbecher et al, 1990;Milner et al, 1990;Fuchs et al, 1995) and protein kinase CK2 (Kraiss et al, 1990;Herrmann et al, 1991;Lorenz et al, 1992) suggesting that cell cycle dependent phosphorylation might control p53 in a ®ne tuning fashion.…”

Section: The P34mentioning

confidence: 99%

“…In addition, p21 WAF1 has also been found to bind to the replication factor PCNA (proliferating-cell nuclear antigen) resulting in an inhibition of DNA synthesis (Mercer et al, 1991;Chen et al, 1995Chen et al, , 1996. In vivo wild-type and mutant p53 is multiply phosphorylated at several sites suggesting a control of p53 function by phosphorylation (Bischo et al, 1990;Meek and Street, 1992;StuÈ rzbecher et al, 1990;Lees-Miller et al, 1992;Ullrich et al, 1993;Milne et al, 1992bMilne et al, , 1994.…”

Section: Introductionmentioning

confidence: 99%

Fine mapping and regulation of the association of p53 with p34cdc2

et al. 1998

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In vivo p53 is multiply phosphorylated by dierent protein kinases suggesting a central role for phosphorylation in modulating p53 function. In addition, p53 was found to be associated with two protein kinases, p34 cdc2 and protein kinase CK2. Here we report the precise mapping of the interaction sites of p53 ± p34 cdc2 complexes. The p34 cdc2 binding site on human p53 maps to one distinct C-terminal site LQIRGRERFE (aa 330 ± 339) close to the corresponding phosphorylation site at serine 315. In order to test whether phosphorylation of p53 might in¯uence the binding of p53 to p34 cdc2 phosphorylation mutants of the C-terminus of p53, which mimick permanent phosphorylation, were tested on their ability to bind to p34 cdc2 in vitro. Substitution of serine 315 (the p34 cdc2 phosphorylation site) with aspartic acid had only little eect on complex formation whereas an exchange of serine 392 (the protein kinase CK2 phosphorylation site) to aspartic acid resulted in a signi®cant reduced relative binding anity of p53 to p34 cdc2 . The same result was obtained when the Cterminus of p53 was phosphorylated by puri®ed protein kinase CK2 prior to examination of complex formation. In addition, the speci®city of the complex formation has been checked by competition experiments with full length p53 proteins and the in¯uence of cyclin B on complex formation was examined.

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“…Despite the fact that the research area of signal transduction has advanced enormously as a whole, there were very few studies of the nucleolar signaling system compared to the nuclear signaling system (Meck and Street, 1992;Inagaki et al, 1994;Buchner, 1995; Diehl and Rai, 1996). Thus, this effort has been directed to focus on the characterization of nucleolar signal cascades or pathways operative in a cell.…”

Section: Introductionmentioning

confidence: 99%

Nucleolus contains signal molecules that constitute membrane-nucleolus linked pathway

Jeong

Kim²,

Lee³

et al. 1998

Exp Mol Med

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Since there have been very few studies on nucleolar signaling, an attempt was made to establish nucleolar signal pathways which link the cell membrane to the nucleolus for the transfer of extracellular signals. Tw o pathways were studied. One was the G s mediated cAMP pathway where two signal molecules were yielded, including R I I and protein kinase A. The other was the G q mediated DAG/IP 3 pathway which yields two signals including protein kinase C and I P 3 / C a 2 + . By the studying isolated nucleoli from resting liver, regenerating liver or weak carcinogen thioacetamide treated liver, it was possible to detect protein kinase A (PKA), protein kinase C (PKC) and R I I subunits. In addition, CK2 was detected. It was found that external signals transmitted through G protein coupled recep-tors could reach into the nucleolus and that physical translocation of signal molecules was an integral step involved in membrane-nucleolus linked pathways. When an i n vitro assay of the above signal molecules w a s carried out using [ -3 2 P ] -AT P, most kinase dependent phosphorylation was via the major CK2 (more than 95%). Therefore, it is suggested that the major CK2 dependent pathway is involved in 'house keeping' for nucleolar integrity and the minor pathways, dependent on PKA, PKC and others, are involved in subtle regulatory mechanisms such as 'extra-house-keeping' activities by nucleolar chromosomal remodeling. IntroductionThe cell nucleus has three transcriptional substructures where pol I dependent transcription is solely performed in the nucleolus, while pol II and pol III dependent transcriptions take place in the nucleoplasm. Being the site of pol I dependent ribosome genesis, the mammalian nucleolus contains a number of post-translational modification mechanisms involved in the activation-deactivation cycle related to the regulation of nucleolar ribosome genesis. These mechanisms are protein methylation (Lischwe et al, 1985), acetylation (Goldknopf et al, 1979), ubiquitination (Goldknopf andBusch, 1978), phosphorylation (Olson et al, 1974), adduct formation to RNA and others (Busch, 1997). Among these molecular mechanisms, protein phosphorylation is a major modification process involved in the regulation of nucleolar function. In earlier works using [ 3 2 P ] -l a b e l i n g techniques of tissue culture, three major nucleolar phosphoproteins were defined. These were 38 kDa nucleophosmin, 110 kDa nucleolin and 140 kDa Nopp140 . More recently, sequence studies of various nucleolar proteins made it possible to define a dozen species of nucleolar phosphoproteins (Busch, 1997).R e c e n t l y, an extensive effort has been made to characterize the mechanism of kinase dependent nucleolar protein phosphorylation involved in various biological conditions. Despite the fact that the research area of signal transduction has advanced enormously as a whole, there were very few studies of the nucleolar signaling system compared to the nuclear signaling system (Meck and Street, 1992;Inagaki et al, 1994;Buchner, 1...

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Nuclear protein phosphorylation and growth control

Cited by 136 publications

References 189 publications

Overexpression of c-Myc and cell immortalization alters c-Myc phosphorylation

Overexpression of c-Myc and cell immortalization alters c-Myc phosphorylation

Fine mapping and regulation of the association of p53 with p34cdc2

Nucleolus contains signal molecules that constitute membrane-nucleolus linked pathway

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