Jayme R Gallegos

Oregon Health and Science University, Portland, OR, United States

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Publications (5)20 Total impact

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    ABSTRACT: p63 is a member of the p53 tumor suppressor family that is critical for epithelial differentiation and also has an important role in cancer progression. Currently, the molecular mechanisms governing regulation of p63 function remain largely unclear. This study identifies a unique E3 ubiquitin ligase for p63, SCF(betaTrCP1). SCF(betaTrCP1) is able to bind p63gamma isoforms, with a higher affinity for the TAp63gamma isoform. Strikingly, co-expression of TAp63gamma and betaTrCP1 leads to the stabilization of TAp63gamma. This stabilization of TAp63gamma leads to up-regulation of p21 at the mRNA and protein level by increased binding of TAp63gamma at the p21 promoter. The up-regulation of p21 causes a subsequent increase in G(1) phase cell cycle arrest. Last, SCF(betaTrCP1) is able to ubiquitylate TAp63gamma, and this ubiquitylation, as well as the increased activity of TAp63gamma, is ablated with the expression of a ubiquitin-deficient mutant of betaTrCP1 (DeltaFbetaTrCP1). Therefore, our study reveals that SCF(betaTrCP1) is an E3 ligase that activates p63 through ubiquitylation.
    Journal of Biological Chemistry 02/2008; 283(1):66-75. · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: p63 is a member of the p53 tumor suppressor family that is critical for epithelial differentiation and also has an important role in cancer progression. Currently, the molecular mechanisms governing regulation of p63 function remain largely unclear. This study identifies a unique E3 ubiquitin ligase for p63, SCFβTrCP1. SCFβTrCP1 is able to bind p63γ isoforms, with a higher affinity for the TAp63γ isoform. Strikingly, co-expression of TAp63γ and βTrCP1 leads to the stabilization of TAp63γ. This stabilization of TAp63γ leads to up-regulation of p21 at the mRNA and protein level by increased binding of TAp63γ at the p21 promoter. The up-regulation of p21 causes a subsequent increase in G1 phase cell cycle arrest. Last, SCFβTrCP1 is able to ubiquitylate TAp63γ, and this ubiquitylation, as well as the increased activity of TAp63γ, is ablated with the expression of a ubiquitin-deficient mutant of βTrCP1 (ΔFβTrCP1). Therefore, our study reveals that SCFβTrCP1 is an E3 ligase that activates p63 through ubiquitylation.
    Journal of Biological Chemistry 01/2008; 283(1):66-75. · 4.60 Impact Factor
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    ABSTRACT: Skp1-cullin-F-box protein (SCF) is a multicomponent E3 ubiquitin (Ub) ligase that ubiquitinates a number of important biologic molecules such as p27, beta-catenin, and IkappaB for proteasomal degradation, thus regulating cell proliferation and survival. One SCF component, SAG/ROC2/Rbx2/Hrt2, a RING finger protein, was first identified as a redox-inducible protein, which, when overexpressed, inhibited apoptosis both in vitro and in vivo. We report here that sensitive to apoptosis gene (SAG), as well as its family member ROC1/Rbx1, bound to the proinactive form of caspase-3 (pro-caspase-3). Binding was likely mediated through F-box protein, beta-transducin repeat-containing protein (beta-TrCP), which binds to the first 38 amino acids of pro-caspase-3. Importantly, beta-TrCP1 expression significantly shortened the protein half-life of pro-caspase-3, whereas expression of a dominant-negative beta-TrCP1 mutant with the F-box domain deleted extended it. An in vitro ubiquitination assay showed that SAG/ROC-SCF(beta-TrCP) promoted ubiquitination of pro-caspase-3. Furthermore, endogenous levels of pro-caspase-3 were decreased by overexpression of SAG/ROC-SCF(beta-TrCP) E3 Ub ligases, but increased on siRNA silencing of SAG, regulator of cullin-1 (ROC1), or beta-TrCPs, leading to increased apoptosis by etoposide and TNF-related apoptosis-inducing ligand through increased activation of caspase-3. Thus, pro-caspase-3 appears to be a substrate of SAG/ROC-SCF(beta-TrCP) E3 Ub ligase, which protects cells from apoptosis through increased apoptosis threshold by reducing the basal level of pro-caspase-3.
    Neoplasia (New York, N.Y.) 01/2007; 8(12):1042-54. · 5.40 Impact Factor
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    Mu-Shui Dai, Yetao Jin, Jayme R Gallegos, Hua Lu
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    ABSTRACT: Protein ubiquitylation has been demonstrated to play a vital role not only in mediating protein turnover but also in modulating protein activity. The stability and activity of the tumor suppressor p53 and of the oncoprotein c-Myc are no exception. Both are regulated through independent ubiquitylation by several E3 ubiquitin ligases. Interestingly, p53 and c-Myc are functionally connected by some of these E3 enzymes and their regulator ARF, although these proteins play opposite roles in controlling cell growth and proliferation. The balance of this complex ubiquitylation network and its disruption during oncogenesis will be the topics of this review.
    Neoplasia (New York, N.Y.) 09/2006; 8(8):630-44. · 5.40 Impact Factor
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    Mu-Shui Dai, Jayme R Gallegos, Hua Lu

Publication Stats

95 Citations
20.00 Total Impact Points

Institutions

  • 2006–2008
    • Oregon Health and Science University
      • Department of Biochemistry & Molecular Biology
      Portland, OR, United States