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ABSTRACT: Pocket proteins negatively regulate transcription of E2F-dependent genes and progression through the G(0)/G(1) transition and the cell cycle restriction point in G(1). Pocket protein repressor activities are inactivated via phosphorylation at multiple Pro-directed Ser/Thr sites by the coordinated action of G(1) and G(1)/S cyclin-dependent kinases. These phosphorylations are reversed by the action of two families of Ser/Thr phosphatases: PP1, which has been implicated in abrupt dephosphorylation of retinoblastoma protein (pRB) in mitosis, and PP2A, which plays a role in an equilibrium that counteracts cyclin-dependent kinase (CDK) action throughout the cell cycle. However, the identity of the trimeric PP2A holoenzyme(s) functioning in this process is unknown. Here we report the identification of a PP2A trimeric holoenzyme containing B55α, which plays a major role in restricting the phosphorylation state of p107 and inducing its activation in human cells. Our data also suggest targeted selectivity in the interaction of pocket proteins with distinct PP2A holoenzymes, which is likely necessary for simultaneous pocket protein activation.
Journal of Biological Chemistry 09/2010; 285(39):29863-73. · 4.77 Impact Factor
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ABSTRACT: Pocket proteins negatively regulate transcription of E2F-dependent genes and progression through the G0/G1 transition and the cell cycle restriction point in G1. Pocket protein repressor activities are inactivated via phosphorylation at multiple Pro-directed Ser/Thr sites by the coordinated
action of G1 and G1/S cyclin-dependent kinases. These phosphorylations are reversed by the action of two families of Ser/Thr phosphatases: PP1,
which has been implicated in abrupt dephosphorylation of retinoblastoma protein (pRB) in mitosis, and PP2A, which plays a
role in an equilibrium that counteracts cyclin-dependent kinase (CDK) action throughout the cell cycle. However, the identity
of the trimeric PP2A holoenzyme(s) functioning in this process is unknown. Here we report the identification of a PP2A trimeric
holoenzyme containing B55α, which plays a major role in restricting the phosphorylation state of p107 and inducing its activation
in human cells. Our data also suggest targeted selectivity in the interaction of pocket proteins with distinct PP2A holoenzymes,
which is likely necessary for simultaneous pocket protein activation.
Journal of Biological Chemistry 09/2010; 285(39):29863-29873. · 4.77 Impact Factor
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Dale S Haines
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ABSTRACT: p97 (also called VCP in metazoans and CDC48 in yeast) is a highly conserved, abundant and essential type II ATPase that functions in numerous ubiquitin signaling dependent processes. p97/Cd48 activities require a growing number of adaptor or accessory proteins that promote interactions with ubiquitinated proteins. p97 has human disease relevance as it is mutated in familial cases of inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD). There is also increasing evidence suggesting that p97 and/or some of its adaptors play a role in cancer. This review will summarize our existing knowledge of the biochemical, molecular and cellular activities of p97-containing complexes, with an ending focus on their potential role in malignancy.
Genes & cancer 09/2010; 1(7):753-763.
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Genes & cancer 07/2010; 1(7):679-80.
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ABSTRACT: UBXD1 is a recently identified adaptor for p97, a highly abundant and conserved member of the AAA family of ATPase that plays pivotal roles in a multitude of cellular processes involving the ubiquitin-proteasome pathway. Very little is known about the biochemical, cellular, and molecular functions of UBXD1. Here we report the generation of two mouse monoclonal antibodies, 5C3-1 and 2F8-24, that recognize UBXD1 using Western blotting, immunoprecipitation, and immunofluorescence.
Hybridoma (2005) 12/2009; 28(6):459-62. · 0.42 Impact Factor
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ABSTRACT: Mga2p90 is an endoplasmic reticulum (ER)-localized transcription factor that is released from the ER membrane by a unique ubiquitin (Ub)-dependent mechanism. Mga2p90 mobilization requires polyubiquitination of its associating membrane-bound Mga2p120 anchor and subsequent Mga2p120-Mga2p90 complex disassembly that is mediated by ATPase Cdc48p and its heteromeric Ub-binding adaptor Npl4p-Ufd1p. Although previous studies have identified the Ub ligase (i.e., Rsp5p) and ligase-binding site on Mga2p120 that play a role in this process, the amino acids of Mga2p120 that are targets of ubiquitination and promote Mga2p90 mobilization are unknown. We have identified, using mass spectrometry analysis of in vitro ubiquitinated Mga2p120-Mga2p90 complex, that lysine residues 983 and 985 contained within the carboxy-terminal domain of Mga2p120 are Rsp5p-directed Ub-conjugation sites. Mutation of these residues as well as proximally located lysine 980 results in suppression of Mga2p120 ubiquitination in vitro and in vivo, inefficient liberation of Mga2p90 by Cdc48p(Npl4p/Ufd1p)in vitro, and ER retention of Mga2p in cells. Moreover, mga2Delta/spt23ts harboring Rsp5p binding and conjugation mga2 mutants express low OLE1 (an Mga2p90 target gene) transcripts and display reduced growth. We conclude that residues 980, 983, and 985 are targets of Rsp5p-induced polyubiquitination and mediate Cdc48p(Npl4p/Ufd1p)-dependent Mga2p90-Mga2p120 separation and Mga2p90 mobilization.
Journal of Molecular Biology 12/2008; 385(3):718-25. · 4.00 Impact Factor
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ABSTRACT: Monitoring Editor: Thomas Sommer The MDM2 ubiquitin ligase is a negative regulator of p53 expression and MDM2 ubiquitination modulates its stability and ligase activity toward p53. A previous study has implicated the AAA ATPase p97 as a modulator of p53 expression. However, it remains unclear which p97 adaptors participate in this process and how a p97-adaptor complex regulates p53. Using an shRNA screen targeting UBX domain (a p97 interaction motif) containing proteins, we show that the p97 adaptor UBXD1 is a p53 pathway regulator. shRNA-mediated depletion of UBXD1 increases p53 levels, stability and activities. Results from UBXD1 transfection and knock-down experiments suggest that a p97-UBXD1 complex modulates p53 by affecting MDM2 ubiquitination and degradation. UBXD1 transfection inhibits MDM2 degradation and ubiquitination and these effects are suppressed with shRNAs directed against p97. Also, shRNA-mediated depletion of p97 or UBXD1 results in enhanced MDM2 ubiquitination and degradation. Interestingly, UBXD1-induced MDM2 stabilization and deubiquitination is suppressed by shRNAs directed against the MDM2 deubiquitinating enzyme HAUSP. Moreover, UBXD1 interacts with p97, MDM2 and HAUSP and mediates binding of p97 to MDM2 and HAUSP in cells. We propose that a p97-UBXD1 complex cooperates with HAUSP in limiting MDM2 ubiquitination and turnover, which in turn contributes to MDM2-dependent p53 degradation.
Molecular biology of the cell 10/2008; 19(11):5029. · 5.98 Impact Factor
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ABSTRACT: Ubiquitination of the human kappa opioid receptor (hKOR) expressed in Chinese hamster ovary (CHO) cells was observed in the presence of the proteasomal inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) and enhanced by the agonists (-)(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidiny) cyclohexyl] benzeneacetamide (U50,488H) and dynorphin A (Dyn A). The dominant-negative (DN) mutants GRK2-K220R and beta-arrestin (319-418), but not dynamin I-K44A, reduced Dyn A-stimulated hKOR ubiquitination, and a phosphorylation-defective hKOR mutant (hKOR-S358N) did not undergo Dyn A-stimulated ubiquitination, indicating that hKOR ubiquitination is enhanced by receptor phosphorylation but not by receptor internalization. A hKOR mutant (hKOR-10 KR) in which all 10 intracellular Lys residues were changed to Arg showed greatly reduced basal and agonist-promoted receptor ubiquitination and substantially decreased Dyn A-induced receptor down-regulation, without changing ligand binding affinity, receptor-G protein coupling, or receptor internalization or desensitization. The ubiquitination sites were further determined to be the three Lys residues in the C-terminal domain. The K63R ubiquitin mutant decreased Dyn A-induced hKOR ubiquitination and down-regulation, but the K48R mutant did not. Expression of HN-CYLD, a DN mutant of deubiquitination enzyme cylindromatosis tumor suppressor gene (CYLD) that breaks Lys63-linked polyubiquitin chain, increased Dyn A-induced hKOR ubiquitination and down-regulation. These results indicate that ubiquitinated hKOR after agonist treatment contains predominantly Lys63-linked polyubiquitin chains and ubiquitination of the hKOR involved in agonist-induced down-regulation.
Molecular pharmacology 05/2008; 73(4):1319-30. · 4.53 Impact Factor
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ABSTRACT: We report a simple approach for determining ion score cutoffs that permit the confident identification of ubiquitinated proteins by tandem mass spectrometry (MS/MS). Initial experiments involving the analysis of gel bands containing multi-Ubiquitin chains with quadrupole time-of-flight and quadrupole ion trap mass spectrometers revealed that standard ion score cutoffs used for database searching were not sufficiently stringent. We also found that false positive and false negative rates (FPR and FNR) varied significantly depending on the cutoff scores used and that appropriate cutoffs could only be determined following a systematic evaluation of false positive rates. When standard cutoff scores were used for the analysis of complex mixtures of ubiquitinated proteins, unacceptably high FPR were observed. Finally, we found that FPR for ubiquitinated proteins are affected by the size of the protein database that is searched. These observations may be applicable for the study of other post-translational modifications.
Journal of Mass Spectrometry 04/2008; 43(3):296-304. · 3.27 Impact Factor
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ABSTRACT: Rsp5p of Saccharomyces cerevisiae is a member of the C2-WW-HECT family of ubiquitin ligases and it interacts with targets via its WW domains. Spt23p and Mga2p are Rsp5p substrates and Rsp5p activates the OLE1 inducing functions of these membrane-localized transcription factors by ubiquitination. Although it is known that Rsp5p binds Mga2p and Spt23p via an imperfect WW domain-binding site (LPKY) that is located within the carboxy-terminal domain of the proteins, it remains unclear which WW domains mediate binding. We show that Rsp5p mutants harboring mutations in single WW domains are Spt23p/Mga2p binding and ubiquitination proficient. This is also the case for WW domains 1/2 and WW domains 1/3 mutants. However, disrupting WW domains 2 and 3 abrogates a physical and functional interaction with substrates in vitro and in cells. We also show that abrogation of WW domains 2 and 3 eliminates the activity of an Rsp5p dominant-negative mutant and an rsp5 WW domain 2/3 mutant is unable to rescue the proliferative defects of rsp5 Delta cells. Interestingly, while rsp5 Delta cells are able to grow on oleic acid containing YPD media, they as well as those transformed with the WW domain 2/3 mutant are unable to proliferate on oleic acid containing synthetic drop-out media. We conclude from these studies that WW domains 2 and 3 of Rsp5p play overlapping roles in binding to the LPKY site on Spt23p and Mga2p. Also, we propose that WW domains 2 and 3 perform yet to be defined essential function(s) outside of the OLE1 pathway when cells are grown in nutrient restrictive media.
The International Journal of Biochemistry & Cell Biology 02/2008; 40(1):147-57. · 4.63 Impact Factor
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ABSTRACT: The INK4 and CIP cyclin-dependent kinase (Cdk) inhibitors (CKI) activate pocket protein function by suppressing Cdk4 and Cdk2, respectively. Although these inhibitors are lost in tumors, deletion of individual CKIs results in modest proliferation defects in murine models. We have evaluated cooperativity between loss of all INK4 family members (using cdk4r24c mutant alleles that confer resistant to INK4 inhibitors) and p21(Waf1/Cip1) in senescence and transformation of mouse embryo fibroblasts (MEF). We show that mutant cdk4r24c and p21 loss cooperate in pRb inactivation and MEF immortalization. Our studies suggest that cdk4r24c mediates resistance to p15(INK4B)/p16(INK4A) that accumulates over passage, whereas loss of p21 suppresses hyperoxia-induced Cdk2 inhibition and pRb dephosphorylation on MEF explantation in culture. Although cdk4r24c and p21 loss cooperate in H-ras(V12)/c-myc-induced foci formation, they are insufficient for oncogene-induced anchorage-independent growth. Interestingly, p21(-/-); cdk4r24c MEFs expressing H-ras(V12) and c-myc display detachment-induced apoptosis and are transformed by c-myc, H-ras(V12), and Bcl-2. We conclude that the INK4 family and p21 loss cooperate in promoting pRb inactivation, cell immortalization, and H-ras(V12)/c-myc-induced loss of contact inhibition. In addition, absence of pRb function renders H-ras(V12) + c-myc-transduced fibroblasts prone to apoptosis when deprived of the extracellular matrix, and oncogene-induced anchorage-independent growth of pocket protein-deficient cells requires apoptotic suppression.
Cancer Research 06/2007; 67(9):4130-7. · 7.86 Impact Factor
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ABSTRACT: Cdc48p is an abundant and conserved member of the AAA ATPase family of molecular chaperones. Cdc48p performs ubiquitin-selective functions, which are mediated by numerous ubiquitin binding adaptors, including the Npl4p-Ufd1p complex. Previous studies suggest that Cdc48p-containing complexes carry out many biochemical activities, including ubiquitination, deubiquitination, protein complex segregation, and targeting of ubiquitinated substrates to the proteasome. The molecular mechanisms by which Cdc48p-containing complexes participate in these processes remain poorly defined. We show here by using physiologically relevant Cdc48p substrates (i.e., endoplasmic membrane-associated/tethered dimers of Mga2p and Spt23p) and in vitro systems with purified proteins that Cdc48p(Npl4p/Ufd1p) binds to and promotes segregation of the tethered proteins via a polyubiquitin signal present on the membrane-bound proteins. Mobilization does not involve retrotranslocation of the associated anchors. These results provide biochemical evidence that Cdc48p(Npl4p/Ufd1p) functions as a polyubiquitin-selective segregase and that a polyubiquitin-Cdc48p pathway modulates protein interactions at cell membranes.
Molecular Cell 03/2007; 25(3):385-97. · 14.18 Impact Factor
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ABSTRACT: Mass spectrometry (MS) coupled to affinity purification is a powerful approach for identifying protein-protein interactions and for mapping post-translational modifications. Prior to MS analysis, affinity-purified proteins are typically separated by gel electrophoresis, visualized with a protein stain, excised, and subjected to in-gel digestion. An inherent limitation of this series of steps is the loss of protein sample that occurs during gel processing. Although methods employing in-solution digestion have been reported, they generally suffer from poor reaction kinetics. In the present study, we demonstrate an application of a microfluidic processing device, termed the Proteomic Reactor, for enzymatic digestion of affinity-purified proteins for liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Use of the Proteomic Reactor enabled the identification of numerous ubiquitinated proteins in a human cell line expressing reduced amounts of the ubiquitin-dependent chaperone, valosin-containing protein (VCP). The Proteomic Reactor is a novel technology that facilitates the analysis of affinity-purified proteins and has the potential to aid future biological studies.
Journal of Proteome Research 02/2007; 6(1):298-305. · 5.11 Impact Factor
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ABSTRACT: Mammalian SWI/SNF-related complexes are ATPase-powered nucleosome remodeling assemblies crucial for proper development and tissue-specific gene expression. The ATPase activity of the complexes is also critical for tumor suppression. The complexes contain seven or more noncatalytic subunits; only one of which, hSNF5/Ini1/BAF47, has been individually identified as a tumor suppressor thus far. The noncatalytic subunits include p270/ARID1A, which is of particular interest because tissue array analysis corroborated by screening of tumor cell lines indicates that p270 may be deficient in as many as 30% of renal carcinomas and 10% of breast carcinomas. The complexes can also include an alternative ARID1B subunit, which is closely related to p270, but the product of an independent gene. The respective importance of p270 and ARID1B in the control of cell proliferation was explored here using a short interfering RNA approach and a cell system that permits analysis of differentiation-associated cell cycle arrest. The p270-depleted cells fail to undergo normal cell cycle arrest on induction, as evidenced by continued synthesis of DNA. These lines fail to show other characteristics typical of arrested cells, including up-regulation of p21 and down-regulation of cyclins. The requirement for p270 is evident separately in both the up-regulation of p21 and the down-regulation of E2F-responsive products. In contrast, the ARID1B-depleted lines behaved like the parental cells in these assays. Thus, p270-containing complexes are functionally distinct from ARID1B-containing complexes. These results provide a direct biological basis to support the implication from tumor tissue screens that deficiency of p270 plays a causative role in carcinogenesis.
Cancer Research 11/2005; 65(20):9236-44. · 7.86 Impact Factor
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ABSTRACT: Proteasome-dependent processing of the endoplasmic reticulum localized transcription factor Spt23p of Saccharomyces cerevisiae generates its transcriptionally competent form and requires the WW domain containing Rsp5p ubiquitin ligase. Although previous studies documented an Rsp5p-Spt23p association in cells, very little is known about the nature of this interaction. We report here the identification of an imperfect type I WW domain-binding site (LPKY) within the carboxyl-terminal region of Spt23p that is required for Rsp5p binding in vitro and in vivo. Deletion of this motif abrogates Rsp5p-induced ubiquitination of Spt23p in vitro and reduces ubiquitination of the Spt23p precursor in yeast. In addition, the Spt23pDeltaLPKY mutant is inefficiently processed and is defective at up-regulating target gene (OLE1) expression in cells. Deletion of the corresponding LPKY site within Mga2p, an Spt23p homologue, also abrogates Rsp5p binding and Rsp5p-dependent ubiquitination in vitro as well as Rsp5p binding and Mga2p polyubiquitination in cells. However, the Mga2pDeltaLPKY mutant undergoes efficient proteasome-dependent processing. These experiments indicate that the LPKY motif of Spt23p is required for Rsp5p binding, Rsp5-induced ubiquitination, proteasome-dependent processing, and its OLE1 inducing function. They also suggest that the LPKY motif of Mga2p is required for Rsp5p binding and ubiquitination, and Rsp5p regulates Mga2p function by a mechanism that is independent of providing the partial degradation signal.
Journal of Biological Chemistry 01/2005; 279(51):53892-8. · 4.77 Impact Factor
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ABSTRACT: Ubiquitination is an increasingly common post-translation modification that controls both the expression and activity of numerous proteins in the eukaryotic cell. One frequent target of the ubiquitin (Ub) modification machinery is transcription factors. Although ubiquitination generally modulates their function by inducing proteasome-dependent degradation, past and recent studies indicate that ubiquitination also regulates nuclear-cytoplasmic trafficking of transcriptional regulators. Ubiquitination is known to modulate transcription factor localization by destroying sequestering proteins and by directly promoting nuclear import and export of modified substrates. This review discusses old and new paradigms relating Ub modification and the control of transcription factor shuttling in and out of the nucleus.
Journal of Cellular Biochemistry 10/2004; 93(1):11-9. · 2.87 Impact Factor
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ABSTRACT: CDK9 is a CDC2-related kinase and the catalytic subunit of the positive-transcription elongation factor b and the Tat-activating kinase. It has recently been reported that CDK9 is a short-lived protein whose levels are regulated during the cell cycle by the SCF(SKP2) ubiquitin ligase complex (R. E. Kiernan et al., Mol. Cell. Biol. 21:7956-7970, 2001). The results presented here are in contrast to those observations. CDK9 protein levels remained unchanged in human cells entering and progressing through the cell cycle from G(0), despite dramatic changes in SKP2 expression. CDK9 levels also remained unchanged in cells exiting from mitosis and progressing through the next cell cycle. Similarly, the levels of CDK9 protein did not change as cells exited the cell cycle and differentiated along various lineages. In keeping with these observations, the kinase activity associated with CDK9 was found to not be regulated during the cell cycle. We have also found that endogenous CDK9 is a very stable protein with a half-life (t(1/2)) of 4 to 7 h, depending on the cell type. In contrast, when CDK9 is overexpressed, it is not stabilized and is rapidly degraded, with a t(1/2) of less than 1 h, depending on the level of expression. Treatment of cells with proteasome inhibitors blocked the degradation of short-lived proteins, such as p27, but did not affect the expression of endogenous CDK9. Ectopic overexpression of SKP2 led to reduction of p27 protein levels but had no effect on the expression of endogenous CDK9. Finally, downregulation of endogenous SKP2 gene expression by interfering RNA had no effect on CDK9 protein levels, whereas p27 protein levels increased dramatically. Therefore, the SCF(SKP2) ubiquitin ligase does not regulate CDK9 expression in a cell cycle-dependent manner.
Molecular and Cellular Biology 09/2003; 23(15):5165-73. · 5.53 Impact Factor
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ABSTRACT: A number of eukaryotic transcription factors are held in a latent state by being embedded in, or tethered to, cellular membranes. Mga2p of Saccharomyces cerevisiae is an endoplasmic reticulum (ER)-localized transcription factor that plays an overlapping role with homologous Spt23p in upregulating expression of OLE1, a gene required for the synthesis of essential oleic acid. Previous studies have documented that proteasome-dependent processing of ER bound 120 kDa Mga2p and Spt23p proteins generates transcriptionally competent 90 kDa polypeptides. In the case of Spt23p90, it is held at the membrane prior to release via a self-interaction with the unprocessed Spt23p120 anchor. It is currently thought that the highly conserved Rsp5p ubiquitin ligase provides the signal for partial degradation of both proteins. Cells lacking Rsp5p function require oleic acid for growth, and Spt23p processing is suppressed in rsp5 Delta cells and in wild-type RSP5 cells upon expression of Rsp5p dominant-negative mutants. We report here that Rsp5p is dispensable for Mga2p90 generation but not for release of the processed product from the ER. In addition, we demonstrate that polyubiquitinated Mga2p120 accumulates in cells lacking Npl4p or proteasome function and Rsp5p is required for Mga2p120 polyubiquitination. Finally, we provide evidence that Mga2p90 and Mga2p120 dimerize and that Rsp5p binds heterodimeric Mga2p complexes both in vitro and in vivo. In light of these experiments, we propose that Rsp5p facilitates Mga2p90 release from the ER by promoting polyubiquitination and Npl4p-proteasome-mediated degradation of the interacting Mga2p120 ER bound anchor.
Current Biology 08/2003; 13(14):1227-33. · 9.65 Impact Factor
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ABSTRACT: The human DNA polymerase epsilon catalytic subunit consists of a 140-kDa N-terminal domain that contains the catalytic activity and a 120-kDa C-terminal domain that binds to the other subunits and to exogenous peptides, including PCNA and MDM2. We report here that recombinant human MDM2 purified from insect cells or Escherichia coli stimulated the activity of DNA polymerase epsilon up to 10- and 40-fold, respectively, but not those of DNA polymerase beta or Klenow fragment of E.coli DNA polymerase I. Kinetic studies indicated that MDM2 increased the maximum velocity of the reaction, but did not change substrate affinities. The stimulation depended upon the interaction of the N-terminal 166 amino acid residues of MDM2 with the C-terminal domain of the full-length catalytic subunit, since the deletion of 166 amino acids from N-terminal of MDM2 or the removal of the C-terminal domain of DNA polymerase epsilon by trypsin digestion or competition for binding to it by the addition of excess C-terminal fragment eliminated the stimulation. Since DNA polymerase epsilon appears to be involved in DNA replication, recombination and repair synthesis, we suggest that MDM2 binding to DNA polymerase epsilon might be part of a reconfiguration process that allows DNA polymerase epsilon to associate with repair/recombination proteins in response to DNA damage.
Nucleic Acids Research 06/2003; 31(9):2451-9. · 8.03 Impact Factor
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ABSTRACT: p130 is a member of the retinoblastoma family of pocket proteins, which includes pRB and p107. Unlike pRB and p107, p130 protein levels decrease dramatically following its hyperphosphorylation starting in the mid-G1 phase of the cell cycle. However, the mechanism leading to p130 downregulation is unknown. We have found that the proteasome inhibitor, lactacystin, inhibited p130 downregulation in T98G cells progressing through the G1/S transition and S phase and that p130 is multiubiquitylated in 293 cells. We have previously shown that ectopic expression of both cyclin D and E induces phosphorylation and downregulation of p130. Since the SKP1/Cul1/SKP2 E3 ubiquitin ligase complex mediates ubiquitylation of substrates previously phosphorylated by cyclin-dependent kinases, we investigated the potential role of this ubiquitin ligase in mediating p130 downregulation. We found that p130 interacts with SKP1, Cul-1 and SKP2 in human 293 cells. We also found that ectopic coexpression of SKP2 and p130 leads to dose-dependent downregulation of p130, reduces p130 protein half-life and induces p130 ubiquitylation in these cells. Moreover, adenoviral-mediated expression of SKP2 accelerates downregulation of endogenous hyperphosphorylated p130 in mitogen-stimulated T98G cells and primary WI38 fibroblasts. We conclude that p130 is a substrate of the SCF(SKP2) ubiquitin ligase and this E3 ligase regulates p130 abundance during the cell cycle.
Oncogene 05/2003; 22(16):2443-51. · 6.37 Impact Factor
