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Gene Review

PSMD9  -  proteasome (prosome, macropain) 26S...

Homo sapiens

Synonyms: 26S proteasome non-ATPase regulatory subunit 9, 26S proteasome regulatory subunit p27, Rpn4, p27
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Disease relevance of PSMD9


High impact information on PSMD9

  • Y88 phosphorylation does not prevent p27 binding to cyclin A/Cdk2 [6].
  • This direct link between transforming tyrosine kinases and p27 may provide an explanation for Cdk kinase activities observed in p27 complexes and for premature p27 elimination in cells that have been transformed by activated tyrosine kinases [6].
  • A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL [6].
  • Instead, it causes phosphorylated Y88 and the entire inhibitory 3(10)-helix of p27 to be ejected from the Cdk2 active site, thus restoring partial Cdk activity [6].
  • The cell-cycle inhibitor p27 is a potential tumor suppressor, but its gene has never been found inactivated in human tumors [7].

Chemical compound and disease context of PSMD9


Biological context of PSMD9

  • The coactivator Bridge-1 (PSMD9) regulates the transcriptional activation of glucose-responsive enhancers in the insulin gene in a dose-dependent manner via PDZ domain-mediated interactions with E2A transcription factors [13].
  • This suggested that the normal expression or control of p27 activity on cell growth might be altered through potential interactions with cyclin D1 [1].
  • When HMBA differentiation was induced in the presence of p27 antisense oligonucleotides, NT2/D1 cells failed to arrest growth properly and, in parallel with the reduction of the anti-apoptotic Bcl-2 gene expression, cells underwent massive programmed cell death [14].
  • Conversely, constitutive expression of p27 into NT2/D1 cells induced a marked reduction in the growth potential of these cells and partially reproduced HMBA-induced modification of surface antigen expression (down-regulation of SSEA-3 expression and up-regulation of VINIS-53 expression) [14].
  • On the other hand, phosphatidylinositol-3-kinase (PI3K)-directed T157 nuclear localization signal (NLS) phosphorylation results in cytoplasmic sequestration of p27, leading to abnormal integrin-mediated proliferation of CD34(+) CML cells [3].

Anatomical context of PSMD9

  • Similar to our previous results by IHC, typical MCLs showed lower expression of p27 when compared to the more highly proliferative blastic cases or cell lines (mean arbitrary units: 58 versus 236 versus 120) [1].
  • We have therefore analyzed the cyclin E content, using Western blotting, in 79 RCC and 12 corresponding kidney cortex tissues as well as the fraction of p27-positive cells in 73 RCCs, using immunohistochemistry [4].
  • The overexpression of the positive regulators (cyclins) or the underexpression of the negative regulators including p27 has been seen in a variety of neoplasms, but their role and interaction in thyroid carcinogenesis is yet to be established [5].
  • High levels of p27 expression were observed in most lymph node tissue samples (93%) obtained from patients with low grade B-cell non-Hodgkin's lymphomas, while expression was low in lymph node tissue taken from all patients with intermediate and high grade B-cell non-Hodgkin's lymphomas [15].
  • The difference in p27 expression in lymphoma tissues was significant among the different histopathological grades of B-cell non-Hodgkin's lymphomas (P<0.01) [15].

Associations of PSMD9 with chemical compounds

  • Moreover, DM p27 strongly inhibits the growth of imatinib-resistant CML cells, compared to the T157A p27 (SM p27) [3].
  • This demonstrates that regulating p27 protein amounts and mTOR/p70S6K are separable functions of tuberin [16].
  • Interestingly, the glutamate-induced reduction of p27 was not dependent on the ubiquitin-proteasome system [17].
  • It is further demonstrated that p27 was phosphorylated on threonine 187 during S phase progression by Cdk2 and that phosphorylated p27 was polyubiquitylated and degraded [18].
  • Cell cycle inhibitors p21 and p27 were significantly upregulated by mevastatin [19].
  • Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not [20].

Physical interactions of PSMD9

  • Using techniques of exhaustive immunoprecipitation, we could demonstrate that most p27 protein was sequestered into complexes containing cyclin D1 [1].
  • Co-precipitation studies revealed an increased amount of p27 complexing with cyclin E-cdk2 during hypoxia than during aerobic cell growth [21].
  • p27/kip1 regulates the G1-S transition of the cell cycle by inhibiting cyclinD-CDK4, cyclinE-CDK2 and cyclinA-CDK2 complexes [22].
  • Coincident with the decrease in kinase activity there was an increase in p27 bound to G1 cyclin/cdk [23].

Enzymatic interactions of PSMD9


Regulatory relationships of PSMD9

  • Moreover, expression of cyclin D3 in thyroid carcinoma cells induced cytoplasmic retention of cotransfected p27 and rescued p27-imposed growth arrest [25].
  • PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model [26].
  • Cks1 and Skp2 mutually promote the binding of each other to a peptide similar to the 19 C-terminal amino acids of p27 containing phosphorylated Thr-187 [27].
  • Taken together, these data provide mechanistic evidence indicating that p27 is primarily involved in oligodendroglial progenitor proliferation by inhibiting CDK2 activity and inducing oligodendrocyte cell-cycle arrest [28].
  • Inactivation of the Nedd8 conjugation pathway by a dominant negative mutant of the Nedd8-conjugating enzyme Nce1/Ubc12 blocks the ubiquitination and degradation of p27 in cell extracts [29].

Other interactions of PSMD9

  • p27 is a cyclin-dependent kinase inhibitor that plays a critical role in regulating G(1)/S progression, and whose activity is, in part, regulated through interactions with D-type cyclins [1].
  • In summary, the results suggest that protein expression of cyclin E and/or p27 is linked to tumor behavior [4].
  • The p27 LI and p16 LI were lower in HCCs with intrahepatic metastasis (p<0.05) [30].
  • In thyroid tumors and cell lines, cyclin D3 expression was associated with cytoplasmic localization of p27 [25].
  • However, we find that 80% of p27-expressing tumors show an uncommon cytoplasmic localization of p27 protein, associated with high Cdk2 activity [25].

Analytical, diagnostic and therapeutic context of PSMD9


  1. Sequestration of p27Kip1 protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL): implications for pathogenesis. Quintanilla-Martinez, L., Davies-Hill, T., Fend, F., Calzada-Wack, J., Sorbara, L., Campo, E., Jaffe, E.S., Raffeld, M. Blood (2003) [Pubmed]
  2. High levels of expression of p27KIP1 and cyclin E in invasive primary malignant melanomas. Bales, E.S., Dietrich, C., Bandyopadhyay, D., Schwahn, D.J., Xu, W., Didenko, V., Leiss, P., Conrad, N., Pereira-Smith, O., Orengo, I., Medrano, E.E. J. Invest. Dermatol. (1999) [Pubmed]
  3. Gene therapy for BCR-ABL(+) human CML with dual phosphorylation resistant p27(Kip1) and stable RNA interference using an EBV vector. Sengupta, A., Banerjee, D., Chandra, S., Banerjee, S. The journal of gene medicine. (2006) [Pubmed]
  4. Cyclin E and p27 protein content in human renal cell carcinoma: clinical outcome and associations with cyclin D. Hedberg, Y., Davoodi, E., Ljungberg, B., Roos, G., Landberg, G. Int. J. Cancer (2002) [Pubmed]
  5. The role of cell cycle regulatory proteins, cyclin D1, cyclin E, and p27 in thyroid carcinogenesis. Wang, S., Wuu, J., Savas, L., Patwardhan, N., Khan, A. Hum. Pathol. (1998) [Pubmed]
  6. Cdk-Inhibitory Activity and Stability of p27(Kip1) Are Directly Regulated by Oncogenic Tyrosine Kinases. Grimmler, M., Wang, Y., Mund, T., Cilensek, Z., Keidel, E.M., Waddell, M.B., Jäkel, H., Kullmann, M., Kriwacki, R.W., Hengst, L. Cell (2007) [Pubmed]
  7. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Loda, M., Cukor, B., Tam, S.W., Lavin, P., Fiorentino, M., Draetta, G.F., Jessup, J.M., Pagano, M. Nat. Med. (1997) [Pubmed]
  8. Cycline-dependent kinase inhibitor, p27 (KIP1), is associated with cholesteatoma. Bayazít, Y.A., Karakök, M., Uçak, R., Kanlíkama, M. Laryngoscope (2001) [Pubmed]
  9. Hypoxia regulation of the cell cycle in malignant melanoma: putative role for the cyclin-dependent kinase inhibitor p27. Murphy, M., Carlson, J.A., Keough, M.P., Claffey, K.P., Signoretti, S., Loda, M. J. Cutan. Pathol. (2004) [Pubmed]
  10. The F-box protein SKP2 mediates androgen control of p27 stability in LNCaP human prostate cancer cells. Lu, L., Schulz, H., Wolf, D.A. BMC Cell Biol. (2002) [Pubmed]
  11. Retinoic acid- and bone morphogenetic protein 4-induced apoptosis in P19 embryonal carcinoma cells requires p27. Glozak, M.A., Rogers, M.B. Exp. Cell Res. (2001) [Pubmed]
  12. MUC4 expression correlates with poor prognosis in small-sized lung adenocarcinoma. Tsutsumida, H., Goto, M., Kitajima, S., Kubota, I., Hirotsu, Y., Wakimoto, J., Batra, S.K., Imai, K., Yonezawa, S. Lung Cancer (2007) [Pubmed]
  13. Overexpression of the coactivator bridge-1 results in insulin deficiency and diabetes. Volinic, J.L., Lee, J.H., Eto, K., Kaur, V., Thomas, M.K. Mol. Endocrinol. (2006) [Pubmed]
  14. Key role of the cyclin-dependent kinase inhibitor p27kip1 for embryonal carcinoma cell survival and differentiation. Baldassarre, G., Barone, M.V., Belletti, B., Sandomenico, C., Bruni, P., Spiezia, S., Boccia, A., Vento, M.T., Romano, A., Pepe, S., Fusco, A., Viglietto, G. Oncogene (1999) [Pubmed]
  15. Protein expression of cell cycle regulator, p27Kip1, correlates with histopathological grade of non-Hodgkin's lymphoma. Kudoh, S., Kumaravel, T.S., Kuramavel, B., Eguchi, M., Asaoku, H., Dohy, H., Fujiwara, M., Sasaki, N., Tanaka, K., Kamada, N. Jpn. J. Cancer Res. (1999) [Pubmed]
  16. Akt regulates nuclear/cytoplasmic localization of tuberin. Rosner, M., Freilinger, A., Hengstschläger, M. Oncogene (2007) [Pubmed]
  17. Calpain activation is required for glutamate-induced p27 down-regulation in cultured cortical neurons. Akashiba, H., Matsuki, N., Nishiyama, N. J. Neurochem. (2006) [Pubmed]
  18. Skp2-mediated p27(Kip1) degradation during S/G(2) phase progression of adipocyte hyperplasia. Auld, C.A., Fernandes, K.M., Morrison, R.F. J. Cell. Physiol. (2007) [Pubmed]
  19. HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2. Wächtershäuser, A., Akoglu, B., Stein, J. Carcinogenesis (2001) [Pubmed]
  20. Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Kim, J., Jonasch, E., Alexander, A., Short, J.D., Cai, S., Wen, S., Tsavachidou, D., Tamboli, P., Czerniak, B.A., Do, K.A., Wu, K.J., Marlow, L.A., Wood, C.G., Copland, J.A., Walker, C.L. Clin. Cancer Res. (2009) [Pubmed]
  21. Molecular analysis of selected cell cycle regulatory proteins during aerobic and hypoxic maintenance of human ovarian carcinoma cells. Krtolica, A., Krucher, N.A., Ludlow, J.W. Br. J. Cancer (1999) [Pubmed]
  22. p27/kip1 expression in oligodendrogliomas and its possible prognostic role. Cavalla, P., Piva, R., Bortolotto, S., Grosso, R., Cancelli, I., Chiò, A., Schiffer, D. Acta Neuropathol. (1999) [Pubmed]
  23. Increased expression of p27Kip1 arrests neuroblastoma cell growth. Matsuo, T., Seth, P., Thiele, C.J. Med. Pediatr. Oncol. (2001) [Pubmed]
  24. Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1. Kortylewski, M., Heinrich, P.C., Mackiewicz, A., Schniertshauer, U., Klingmüller, U., Nakajima, K., Hirano, T., Horn, F., Behrmann, I. Oncogene (1999) [Pubmed]
  25. Overexpressed cyclin D3 contributes to retaining the growth inhibitor p27 in the cytoplasm of thyroid tumor cells. Baldassarre, G., Belletti, B., Bruni, P., Boccia, A., Trapasso, F., Pentimalli, F., Barone, M.V., Chiappetta, G., Vento, M.T., Spiezia, S., Fusco, A., Viglietto, G. J. Clin. Invest. (1999) [Pubmed]
  26. PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Weng, L.P., Brown, J.L., Eng, C. Hum. Mol. Genet. (2001) [Pubmed]
  27. Three different binding sites of Cks1 are required for p27-ubiquitin ligation. Sitry, D., Seeliger, M.A., Ko, T.K., Ganoth, D., Breward, S.E., Itzhaki, L.S., Pagano, M., Hershko, A. J. Biol. Chem. (2002) [Pubmed]
  28. Ectopic expression of p27Kip1 in oligodendrocyte progenitor cells results in cell-cycle growth arrest. Tikoo, R., Osterhout, D.J., Casaccia-Bonnefil, P., Seth, P., Koff, A., Chao, M.V. J. Neurobiol. (1998) [Pubmed]
  29. A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination. Podust, V.N., Brownell, J.E., Gladysheva, T.B., Luo, R.S., Wang, C., Coggins, M.B., Pierce, J.W., Lightcap, E.S., Chau, V. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  30. Expression of the G1-S modulators in hepatitis B virus-related hepatocellular carcinoma and dysplastic nodule: association of cyclin D1 and p53 proteins with the progression of hepatocellular carcinoma. Choi, Y.L., Park, S.H., Jang, J.J., Park, C.K. J. Korean Med. Sci. (2001) [Pubmed]
  31. p27/Kip1 mutation found in breast cancer. Spirin, K.S., Simpson, J.F., Takeuchi, S., Kawamata, N., Miller, C.W., Koeffler, H.P. Cancer Res. (1996) [Pubmed]
  32. Prognostic role of p27Kip1 and apoptosis in human breast cancer. Wu, J., Shen, Z.Z., Lu, J.S., Jiang, M., Han, Q.X., Fontana, J.A., Barsky, S.H., Shao, Z.M. Br. J. Cancer (1999) [Pubmed]
  33. Cyclin D3 immunoreactivity in gastrointestinal stromal tumors is independent of cyclin D3 gene amplification and is associated with nuclear p27 accumulation. Pruneri, G., Mazzarol, G., Fabris, S., Del Curto, B., Bertolini, F., Neri, A., Viale, G. Mod. Pathol. (2003) [Pubmed]
  34. Cyclin-dependant kinase inhibitors CIP1 (p21) and KIP1 (p27) in ovarian cancer. Schmider-Ross, A., Pirsig, O., Gottschalk, E., Denkert, C., Lichtenegger, W., Reles, A. J. Cancer Res. Clin. Oncol. (2006) [Pubmed]
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