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Gene Review

PSMC4  -  proteasome (prosome, macropain) 26S...

Homo sapiens

Synonyms: 26S protease regulatory subunit 6B, 26S proteasome AAA-ATPase subunit RPT3, MB67-interacting protein, MGC13687, MGC23214, ...
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Disease relevance of PSMC4

  • We have used immunoblotting and immunohistochemical analysis to see whether there is phosphorylation of p70 S6 kinase, and the ribosomal S6 protein in angiomyolipomas occurring in tuberous scierosis [1].
  • The complete nucleotide sequences of genomic segments S1 to S6 from Dendrolimus punctatus cypovirus 1 (DpCPV-1) have been determined [2].
  • Long-term pretreatment of CEF with PMA only partially attenuated the stimulation of the S6 protein kinase activity by serum or by expression of the Rous sarcoma virus transforming gene product, pp60v-src [3].
  • Importantly, we identified Akt activation as a novel prognostic indicator of decreased event-free or overall survival in neuroblastoma, whereas phosphorylation of S6 ribosomal protein or ERK had no prognostic effect [4].
  • In non-demented patients that die of bronchopneumonia, the areas of the cortex which are depleted in neuronin S-6 are consistent with the pattern of the 'selective vulnerability' of the cortex to hypoxia, suggesting that the terminal state can also affect the neocortex [5].

High impact information on PSMC4

  • Rapamycin also interfered with signaling by these S6 kinases, blocking serum-stimulated S6 phosphorylation and delaying entry of Swiss 3T3 cells into S phase [6].
  • Although the cellular role of S6 phosphorylation is still not fully clear, studies on p70S6k and its activation have revealed the existence of a novel signalling pathway, clues to the mechanism of action of certain immunosuppressants and insights into the control of gene expression at the levels of transcription and translation [7].
  • The S6 peptide is shown to be a competitive inhibitor of Hoechst 33258, and it is concluded that the SPKK repeat binds to DNA in its minor groove with a binding constant, KS6 = 1.67 X 10(10) M-1 [8].
  • A special type of beta-turn structural motif has been proposed for this sequence, and it has been shown that a segment of the sea urchin sperm H1 N terminus, which has six repeats of the motif (S6 peptide), binds to DNA and competes with the DNA binding drug Hoechst 33258 [9].
  • Here, we demonstrate by quantitative analysis of hydroxyl radical footprints that the synthetic oligopeptide, SPRKSPRK (S2), and the S6 peptide prefer to bind to the minor groove of DNA at the same A/T-rich sites [9].

Chemical compound and disease context of PSMC4

  • METHODS: S6K1/2 expression and phosphorylated ribosomal S6 protein (phS6) content have been detected in formalin fixed, paraffin embedded sections of 50 human endometrial adenocarcinomas with different grade of differentiation and in 13 normal endometrial tissues using immunohistochemical approach with following semiquantitative analysis [10].

Biological context of PSMC4

  • Deletional mutagenesis shows that the C-terminal 78 amino acids of the S6 ATPase are necessary and sufficient to mediate the interaction with gankyrin [11].
  • Another ribosomal S6 protein kinase, p70S6K, is expressed by platelets but shows no change in kinase activity upon platelet activation with thrombin [12].
  • We found that ribosomal protein S6 (S6), which exerts translational control of protein synthesis and is required for cell growth, is hyperphosphorylated in the smooth muscle-like cell lesions of LAM patients compared with smooth muscle cells from normal human blood vessels and trachea [13].
  • Each segment of S1 to S6 possess a single open reading frame [2].
  • It physiologically phosphorylates the S6 protein of the 40s ribosomal subunit in response to mitogenic stimuli and is a downstream component of the rapamycin-sensitive pathway, which includes the 12-kDa FK506 binding protein and includes rapamycin and the 12-kDa FK506 binding protein target 1 [14].

Anatomical context of PSMC4


Associations of PSMC4 with chemical compounds

  • These data demonstrate that tuberin negatively regulates the activity of S6 and p70S6K specifically, and suggest a potential mechanism for abnormal cell growth in LAM [13].
  • Phosphoamino acid analysis revealed that the phosphorylation of Manduca prothoracic gland S6 is limited exclusively to serine residues [20].
  • Thus, leucine acting through an mTOR-dependent pathway stimulates the translation of specific mRNAs both by increasing the availability of eIF4E and by stimulating phosphorylation of S6 [21].
  • To measure S6 phosphorylation in vivo, 3T3/HIR cells were preincubated with [32P]Pi and treated with insulin and MA-5 [22].
  • Both PMA and carbachol promoted the phosphorylation of the ribosomal protein S6 and activated an S6 protein kinase in the normal but not in the protein kinase C-deficient cells [23].

Physical interactions of PSMC4

  • Gankyrin interacts with the S6 proteasomal ATPase and accelerates the degradation of the tumor suppressor Rb [24].

Regulatory relationships of PSMC4

  • Re-introduction of wild type tuberin into LAMD-SM, ELT3, and ERC15 cells abolished phosphorylation of S6 and significantly inhibited p70S6K activity and DNA synthesis [13].

Other interactions of PSMC4

  • Gankyrin interacts with both free and regulatory complex-associated S6 ATPase and is not stably associated with the 26 S particle [11].
  • Activator complexes containing the proteasomal regulatory ATPases S10b (SUG2) and S6 (TBP1) in different tissues and organisms [25].
  • S4, S6, S10b, and S6' displayed specific binding to components of the regulatory complex separated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) or two-dimensional PAGE [26].
  • In parallel, TSC2-/- smooth muscle cells (ELT3) and TSC2-/- epithelial cells (ERC15) also exhibited hyperphosphorylation of S6, constitutive activation of p70S6K, and increased basal DNA synthesis [13].
  • Rapamycin, an immunosuppressant, inhibited hyperphosphorylation of S6, p70S6K activation, and DNA synthesis in LAMD-SM cells [13].

Analytical, diagnostic and therapeutic context of PSMC4


  1. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. El-Hashemite, N., Zhang, H., Henske, E.P., Kwiatkowski, D.J. Lancet (2003) [Pubmed]
  2. Genomic sequence analyses of segments 1 to 6 of Dendrolimus punctatus cytoplasmic polyhedrosis virus. Zhao, S.L., Liang, C.Y., Hong, J.J., Peng, H.Y. Arch. Virol. (2003) [Pubmed]
  3. Stimulation of ribosomal protein S6 kinase activity by pp60v-src or by serum: dissociation from phorbol ester-stimulated activity. Blenis, J., Erikson, R.L. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  4. Activation of Akt predicts poor outcome in neuroblastoma. Opel, D., Poremba, C., Simon, T., Debatin, K.M., Fulda, S. Cancer Res. (2007) [Pubmed]
  5. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Bowen, D.M., Smith, C.B., White, P., Davison, A.N. Brain (1976) [Pubmed]
  6. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Chung, J., Kuo, C.J., Crabtree, G.R., Blenis, J. Cell (1992) [Pubmed]
  7. p70 S6 kinase: an enigma with variations. Proud, C.G. Trends Biochem. Sci. (1996) [Pubmed]
  8. SPKK, a new nucleic acid-binding unit of protein found in histone. Suzuki, M. EMBO J. (1989) [Pubmed]
  9. 'SPKK' motifs prefer to bind to DNA at A/T-rich sites. Churchill, M.E., Suzuki, M. EMBO J. (1989) [Pubmed]
  10. Immunohistochemical analysis of S6K1 and S6K2 expression in endometrial adenocarcinomas. Lyzogubov, V.V., Lytvyn, D.I., Dudchenko, T.M., Lubchenko, N.V., Pogrybniy, P.V., Nespryadko, S.V., Vinnitska, A.B., Usenko, V.S., Gout, I.T., Filonenko, V.V. Experimental oncology. (2004) [Pubmed]
  11. Gankyrin is an ankyrin-repeat oncoprotein that interacts with CDK4 kinase and the S6 ATPase of the 26 S proteasome. Dawson, S., Apcher, S., Mee, M., Higashitsuji, H., Baker, R., Uhle, S., Dubiel, W., Fujita, J., Mayer, R.J. J. Biol. Chem. (2002) [Pubmed]
  12. p42 mitogen-activated protein kinase and p90 ribosomal S6 kinase are selectively phosphorylated and activated during thrombin-induced platelet activation and aggregation. Papkoff, J., Chen, R.H., Blenis, J., Forsman, J. Mol. Cell. Biol. (1994) [Pubmed]
  13. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). Goncharova, E.A., Goncharov, D.A., Eszterhas, A., Hunter, D.S., Glassberg, M.K., Yeung, R.S., Walker, C.L., Noonan, D., Kwiatkowski, D.J., Chou, M.M., Panettieri, R.A., Krymskaya, V.P. J. Biol. Chem. (2002) [Pubmed]
  14. Neurabin is a synaptic protein linking p70 S6 kinase and the neuronal cytoskeleton. Burnett, P.E., Blackshaw, S., Lai, M.M., Qureshi, I.A., Burnett, A.F., Sabatini, D.M., Snyder, S.H. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  15. Tat-binding protein 7 is a subunit of the 26S protease. Dubiel, W., Ferrell, K., Rechsteiner, M. Biol. Chem. Hoppe-Seyler (1994) [Pubmed]
  16. Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Amornphimoltham, P., Patel, V., Sodhi, A., Nikitakis, N.G., Sauk, J.J., Sausville, E.A., Molinolo, A.A., Gutkind, J.S. Cancer Res. (2005) [Pubmed]
  17. Identification of phosphoprotein NP33 as a nucleus-associated ribosomal S6 protein and its phosphorylation in hematopoietic cells. Macfarlane, D.E., Gailani, D. Cancer Res. (1990) [Pubmed]
  18. Human HSP27 is phosphorylated at serines 78 and 82 by heat shock and mitogen-activated kinases that recognize the same amino acid motif as S6 kinase II. Landry, J., Lambert, H., Zhou, M., Lavoie, J.N., Hickey, E., Weber, L.A., Anderson, C.W. J. Biol. Chem. (1992) [Pubmed]
  19. Ribosomal protein S6 phosphorylation and function during late gestation liver development in the rat. Boylan, J.M., Anand, P., Gruppuso, P.A. J. Biol. Chem. (2001) [Pubmed]
  20. Molecular cloning, developmental expression, and phosphorylation of ribosomal protein S6 in the endocrine gland responsible for insect molting. Song, Q., Gilbert, L.I. J. Biol. Chem. (1997) [Pubmed]
  21. Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. Kimball, S.R., Shantz, L.M., Horetsky, R.L., Jefferson, L.S. J. Biol. Chem. (1999) [Pubmed]
  22. Monoclonal antibodies mimic insulin activation of ribosomal protein S6 kinase without activation of insulin receptor tyrosine kinase. Studies in cells transfected with normal and mutant human insulin receptors. Sung, C.K., Maddux, B.A., Hawley, D.M., Goldfine, I.D. J. Biol. Chem. (1989) [Pubmed]
  23. Protein kinase C-dependent and -independent pathways of proto-oncogene induction in human astrocytoma cells. Blackshear, P.J., Stumpo, D.J., Huang, J.K., Nemenoff, R.A., Spach, D.H. J. Biol. Chem. (1987) [Pubmed]
  24. The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Higashitsuji, H., Higashitsuji, H., Itoh, K., Sakurai, T., Nagao, T., Sumitomo, Y., Sumitomo, H., Masuda, T., Dawson, S., Shimada, Y., Mayer, R.J., Fujita, J. Cancer Cell (2005) [Pubmed]
  25. Activator complexes containing the proteasomal regulatory ATPases S10b (SUG2) and S6 (TBP1) in different tissues and organisms. Hastings, R., Walker, G., Eyheralde, I., Dawson, S., Billett, M., Mayer, R.J. Mol. Biol. Rep. (1999) [Pubmed]
  26. Specific interactions between ATPase subunits of the 26 S protease. Richmond, C., Gorbea, C., Rechsteiner, M. J. Biol. Chem. (1997) [Pubmed]
  27. Localisation of 26S proteasomes with different subunit composition in insect muscles undergoing programmed cell death. Löw, P., Hastings, R.A., Dawson, S.P., Sass, M., Billett, M.A., Mayer, R.J., Reynolds, S.E. Cell Death Differ. (2000) [Pubmed]
  28. Activation of the pp90rsk and mitogen-activated serine/threonine protein kinases by ionizing radiation. Kharbanda, S., Saleem, A., Shafman, T., Emoto, Y., Weichselbaum, R., Kufe, D. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  29. The primary structure of the human ribosomal protein S6 derived from a cloned cDNA. Heinze, H., Arnold, H.H., Fischer, D., Kruppa, J. J. Biol. Chem. (1988) [Pubmed]
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