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PGGT1B  -  protein geranylgeranyltransferase type I,...

Homo sapiens

Synonyms: BGGI, GGTI, GGTase-I-beta, Geranylgeranyl transferase type I subunit beta, Geranylgeranyl transferase type-1 subunit beta, ...
 
 
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Disease relevance of PGGT1B

  • Although FTI/GGTI combinations elicit a greater apoptotic response than either agent alone in vitro, the toxicity associated with GGTI treatment in vivo limits the duration of treatment and, thus, may limit the therapeutic benefit that might be gained by inhibiting oncogenic Ki-Ras through dual prenyltransferase inhibitor therapy [1].
 

High impact information on PGGT1B

  • Continuous infusion (72 h) of varying doses of GGTI in conjunction with a high, fixed dose of FTI causes a dose-dependent inhibition of Ki-Ras prenylation [1].
  • An inhibitor of geranylgeranyltransferase inhibitor (GGTI 298) further induced the cytokine and lovastatin-mediated iNOS expression, suggesting the involvement of geranylgeranylated proteins in the regulation of iNOS [2].
  • This study investigates the effects of (i) inhibiting geranylgeranylation (GG) in human mesangial cell (HMC) proliferation and apoptosis, using GGTI 298, a specific inhibitor of GG and (ii) lovastatin, an HMG-coacetyl A-reductase inhibitor, which depletes the availability of prenylation substrates [3].
  • In all cases, FTI/GGTI cotreatment led to synergistic cytotoxic effects in both myeloid cell lines (5/5) and primary AML cells (6/6) [4].
  • GGTI treatment of NB-4 cells resulted in an accumulation of cells in G(0)/G(1), whereas FTI L-744,832 primarily caused an increase in G(2)/M [4].
 

Biological context of PGGT1B

  • GGTI 298 (10-20 muM) and lovastatin (5-10 muM) potently inhibited platelet-derived growth factor and serum-stimulated HMC proliferation and induced apoptosis [3].
 

Anatomical context of PGGT1B

  • To address this issue, the effects of FTI, GGTI and lovastatin alone and in combination were analysed in MM cell lines and primary cells [5].
 

Associations of PGGT1B with chemical compounds

  • GGTI 298, lovastatin, and C3 exoenzyme inhibit HMC proliferation and promote apoptosis [3].
  • Furthermore, the statin effects were reversed by mevalonate and mimicked by the geranylgeranyl transferase inhibitor (GGTI), whereas the farnesyl transeferase inhibitor (FTI) had no effect [6].
  • In addition, the prenylation inhibitors FTI R115777 and GGTI 2147 increased apoptosis in these cells [7].
  • Our aim was to evaluate the consequences of very mild forms of gestational glucose intolerance, defined by an elevated 50-g glucose challenge test followed by a normal oral glucose tolerance test, using the more restrictive Carpenter and Coustan's criteria (Borderline Gestational Glucose Intolerance, BGGI) [8].
  • GGTI, an inhibitor of protein geranylgeranylation, mimicked the effect of simvastatin on apoptosis and interfered with the membrane localization of RhoA [9].
 

Analytical, diagnostic and therapeutic context of PGGT1B

  • While preclinical studies investigating prenylation inhibitors, such as lovastatin, farnesyltransferase inhibitors (FTI) and geranylgeranyltransferase inhibitors (GGTI), have been promising, recent phase I/II clinical trials with FTI R115777 were disappointing, suggesting resistance to FTI monotherapy [5].

References

  1. Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Lobell, R.B., Omer, C.A., Abrams, M.T., Bhimnathwala, H.G., Brucker, M.J., Buser, C.A., Davide, J.P., deSolms, S.J., Dinsmore, C.J., Ellis-Hutchings, M.S., Kral, A.M., Liu, D., Lumma, W.C., Machotka, S.V., Rands, E., Williams, T.M., Graham, S.L., Hartman, G.D., Oliff, A.I., Heimbrook, D.C., Kohl, N.E. Cancer Res. (2001) [Pubmed]
  2. Rho A negatively regulates cytokine-mediated inducible nitric oxide synthase expression in brain-derived transformed cell lines: negative regulation of IKKalpha. Rattan, R., Giri, S., Singh, A.K., Singh, I. Free Radic. Biol. Med. (2003) [Pubmed]
  3. The role of geranylgeranylated proteins in human mesangial cell proliferation. Khwaja, A., Sharpe, C.C., Noor, M., Hendry, B.M. Kidney Int. (2006) [Pubmed]
  4. Synergistic cytotoxic effects in myeloid leukemia cells upon cotreatment with farnesyltransferase and geranylgeranyl transferase-I inhibitors. Morgan, M.A., Wegner, J., Aydilek, E., Ganser, A., Reuter, C.W. Leukemia (2003) [Pubmed]
  5. Combining prenylation inhibitors causes synergistic cytotoxicity, apoptosis and disruption of RAS-to-MAP kinase signalling in multiple myeloma cells. Morgan, M.A., Sebil, T., Aydilek, E., Peest, D., Ganser, A., Reuter, C.W. Br. J. Haematol. (2005) [Pubmed]
  6. Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages. Veillard, N.R., Braunersreuther, V., Arnaud, C., Burger, F., Pelli, G., Steffens, S., Mach, F. Atherosclerosis (2006) [Pubmed]
  7. Depletion of substrates for protein prenylation increases apoptosis in human periovulatory granulosa cells. Rung, E., Friberg, P.A., Bergh, C., Billig, H. Mol. Reprod. Dev. (2006) [Pubmed]
  8. Evaluating the therapeutic approach in pregnancies complicated by borderline glucose intolerance: a randomized clinical trial. Bonomo, M., Corica, D., Mion, E., Gonçalves, D., Motta, G., Merati, R., Ragusa, A., Morabito, A. Diabet. Med. (2005) [Pubmed]
  9. Simvastatin potentiates tumor necrosis factor alpha-mediated apoptosis of human vascular endothelial cells via the inhibition of the geranylgeranylation of RhoA. Tang, D., Park, H.J., Georgescu, S.P., Sebti, S.M., Hamilton, A.D., Galper, J.B. Life Sci. (2006) [Pubmed]
 
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