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Gene Review

SUB1  -  SUB1 homolog (S. cerevisiae)

Homo sapiens

Synonyms: Activated RNA polymerase II transcriptional coactivator p15, P15, PC4, Positive cofactor 4, RPO2TC1, ...


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Disease relevance of SUB1


Psychiatry related information on SUB1

  • The analysis of seven patients with interstitial deletions and one with a small terminal deletion confirmed the existence of two critical regions, one for dysmorphism and mental retardation in p15.2 and the other for the cat cry in p15 [4].

High impact information on SUB1

  • A novel positive cofactor (PC4) purified from the human USA fraction effected a marked enhancement (up to 85-fold) of GAL4-AH-dependent transcription in conjunction with TFIID and other general factors [5].
  • Purification, cloning, and characterization of a human coactivator, PC4, that mediates transcriptional activation of class II genes [5].
  • Isolation of a corresponding cDNA identified PC4 as a 127 residue single-stranded DNA-binding protein with serine-rich regions near the N-terminus [5].
  • Our investigations of mammalian class II gene transcription resulted in identification, purification, and cloning of the corresponding cDNA of a cellular factor (p15) that mediates the effects of several distinct activators on transcription in vitro [6].
  • A cytogenetic deletion in chromosome 3 (p14-p23) was reported in small-cell lung cancer (SCLC) by Whang-Peng et al [7].

Chemical compound and disease context of SUB1

  • Mutation of cysteine residues in either zinc-binding domain of the p7 portion of p15 does not alter the RNA-dependent cleavage, but mutation of three basic residues located between the zinc-binding domains blocks HIV protease susceptibility [8].
  • The intracellular precursor Pr180gag-pol was also cleaved by p15, whereas the intracellular glycoprotein precursors of avian RNA tumor viruses, Pr92env, remained unaffected by p15 under all conditions tested [9].
  • Hypermethylation of the three genes was studied in 81 patients with therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing [10].
  • METHODS: The objective of this study was to investigate the relation of age and success of diazepam (DZP) treatment in the lithium-pilocarpine model of secondarily generalized seizure in the rat by using naïve rats of three age groups, roughly corresponding to the human ages of infancy (P15), adolescence (P20), and adult (P60) [11].
  • Several monoclonal antibodies to different epitopes of the two major core proteins of visna virus, p25 and p15, were tested with the Avidin-Biotin immunostaining method on formaldehyde-fixed and paraffin-embedded sections of brains from patients with acquired immune deficiency syndrome (AIDS) who had shown neurological symptoms at death [12].

Biological context of SUB1

  • Evolutionarily conserved interaction between CstF-64 and PC4 links transcription, polyadenylation, and termination [13].
  • Here we show that PC4 coactivator function, in contrast to basal (activator-independent) transcription, is dependent both on TATA binding protein (TBP)-associated factors (TAFs) in TFIID and on TFIIH [14].
  • All other SUBs (SUB1, SUB3-7) are dermatophyte-specific and have apparently emerged more recently, through successive gene duplication events [15].
  • A substrate, SUB1 (succinyl-Ala-Ala-Pro-Phe-p-nitroanilide), was used during enzyme kinetics experiments [16].
  • Topoisomerase I and PC4 both enhance TFIIIC interactions with down-stream promoter regions and promote multiple, but not single, round transcription by RNA polymerase III from preformed preinitiation complexes [17].
  • Here we show that Positive Cofactor 4 (PC4) has an early and deterministic role in DNA repair pathway re-routing    [18].

Anatomical context of SUB1

  • Further analysis of general coactivator requirements showed that selective removal of PC4 from the essential USA fraction severely impairs Oct-1 and OCA-B function in a cell-free system reconstituted with partially purified factors [19].
  • Enforced expression of p14 NF-E4 in the K562 fetal/erythroid cell line, and in primary erythroid cord blood progenitors, results in repression of gamma-gene expression [20].
  • This effect is specific, as enforced expression of a mutant form of p14 NF-E4, which fails to interact with CP2, also fails to repress gamma-gene expression in K562 cells [20].
  • These results suggest that in class II+ mature B-cells NF-Y is associated with the protein cofactor, PC4, which may play an important role in NF-Y-mediated transcriptional control of class II genes [21].
  • CONCLUSIONS: These results suggest that PC4/TIS7 plays a role in intracellular signaling in the intestinal epithelium during the adaptive response, possibly as a common downstream effector for several intestinotrophic growth factors [22].

Associations of SUB1 with chemical compounds

  • Instead, the protein kinase CK2 and the coactivator PC4 establish DPE-specific transcription in an in vitro transcription system containing TFIID, Mediator, and the GTFs [23].
  • Serum free fatty acid (FFA) and glycerol levels were significantly lower during SUBs 2, 3, and 4 as compared with SUB1 (P < 0.001) [24].
  • Here we show that two positive cofactors (PC2 and PC4) derived from the upstream stimulatory activity (USA) cofactor fraction act synergistically to mediate thyroid hormone (T3)-dependent activation either by TR or by a TR-TRAP complex in an in vitro system reconstituted with purified factors and DNA templates [25].
  • Mass spectral analysis revealed that there are at least two lysine residues acetylated in PC4, as a result of which its DNA binding activity is stimulated [26].
  • Based on our observations on cells grown with GM-CSF and 5-aza-2'-deoxycytidine, DNA methylation of the p15 promoter region CpG island appears to be associated with proliferation rather than differentiation of normal human myeloid progenitors [27].

Physical interactions of SUB1


Other interactions of SUB1

  • A dynamic model for PC4 coactivator function in RNA polymerase II transcription [14].
  • In all, 5 (8.9%) CLL samples harboured concurrent methylation of both p15 and p16 [30].
  • We have analyzed the mechanisms underlying stimulation of transcription by the activator GAL4-AH and the recombinant coactivator p15 (PC4) [29].
  • Interaction between PC4 and NF-Y was mapped to the C-terminal region of PC4, and the subunit interaction subdomain of the highly conserved DNA binding-subunit interaction domain (DBD) of NF-YA [21].
  • We also demonstrated that PC4 can stimulate p53- and p53Delta30-mediated transactivation from a p53-responsive promoter [31].

Analytical, diagnostic and therapeutic context of SUB1

  • NMR titration experiments using various protein and DNA substrates of the individual domains and the full-length PC4 revealed local conformational or environmental changes in both the structured and unstructured subdomains, which are interpreted to be caused by inter- and intramolecular interactions [32].
  • Our results support a possible involvement of PC4 in AAV replication and may be used in efficient production of AAV vectors for gene therapy [2].
  • Unlike experimentally induced virus-negative leukaemias and sarcomas of other species, LSA cells from FeLV-negative LSA cats lack any FeLV proteins, including p15 or p12, and complete functional copies of FeLV provirus and thus do not produce FeLV when grown in cell culture [33].
  • We prospectively analyzed p15 and p16 promoter methylation patterns using methylation-specific polymerase chain reaction (PCR) in patients with adult and childhood acute leukemias and studied the association of methylation patterns with chromosomal abnormalities and prognostic variables [34].
  • Seropositivity for antibodies against the envelope (gp41) and gag antigens (p15, p24) was determined by Western blot using disrupted HTLV-III virions [35].


  1. Functional interaction between the HIV transactivator Tat and the transcriptional coactivator PC4 in T cells. Holloway, A.F., Occhiodoro, F., Mittler, G., Meisterernst, M., Shannon, M.F. J. Biol. Chem. (2000) [Pubmed]
  2. Transcription-positive cofactor 4 enhances rescue of adeno-associated virus genome from an infectious clone. Muramatsu, S., Handa, A., Kajigaya, S., Brown, K.E. J. Gen. Virol. (1998) [Pubmed]
  3. Retraction. The TSG101 tumor susceptibility gene is located in chromosome 11 band p15 and is mutated in human breast cancer. Li, L., Francke, U., Cohen, S.N. Cell (1998) [Pubmed]
  4. Clinical and molecular characterisation of 80 patients with 5p deletion: genotype-phenotype correlation. Mainardi, P.C., Perfumo, C., Calì, A., Coucourde, G., Pastore, G., Cavani, S., Zara, F., Overhauser, J., Pierluigi, M., Bricarelli, F.D. J. Med. Genet. (2001) [Pubmed]
  5. Purification, cloning, and characterization of a human coactivator, PC4, that mediates transcriptional activation of class II genes. Ge, H., Roeder, R.G. Cell (1994) [Pubmed]
  6. A novel mediator of class II gene transcription with homology to viral immediate-early transcriptional regulators. Kretzschmar, M., Kaiser, K., Lottspeich, F., Meisterernst, M. Cell (1994) [Pubmed]
  7. Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Naylor, S.L., Johnson, B.E., Minna, J.D., Sakaguchi, A.Y. Nature (1987) [Pubmed]
  8. Cleavage of p15 protein in vitro by human immunodeficiency virus type 1 protease is RNA dependent. Sheng, N., Erickson-Viitanen, S. J. Virol. (1994) [Pubmed]
  9. Effect of p15-associated protease from an avian RNA tumor virus on avian virus-specific polyprotein precursors. Moelling, K., Scott, A., Dittmar, K.E., Owada, M. J. Virol. (1980) [Pubmed]
  10. Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Christiansen, D.H., Andersen, M.K., Pedersen-Bjergaard, J. Leukemia (2003) [Pubmed]
  11. Diazepam terminates brief but not prolonged seizures in young, naïve rats. Goodkin, H.P., Liu, X., Holmes, G.L. Epilepsia (2003) [Pubmed]
  12. Immunohistochemical staining of cells in the brain of a patient with acquired immune deficiency syndrome (AIDS) with a monoclonal antibody to visna virus. Georgsson, G., Houwers, D.J., Stefánsson, K., Pálsson, P.A., Pétursson, G. Acta Neuropathol. (1987) [Pubmed]
  13. Evolutionarily conserved interaction between CstF-64 and PC4 links transcription, polyadenylation, and termination. Calvo, O., Manley, J.L. Mol. Cell (2001) [Pubmed]
  14. A dynamic model for PC4 coactivator function in RNA polymerase II transcription. Malik, S., Guermah, M., Roeder, R.G. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  15. Secreted subtilisin gene family in Trichophyton rubrum. Jousson, O., Léchenne, B., Bontems, O., Mignon, B., Reichard, U., Barblan, J., Quadroni, M., Monod, M. Gene (2004) [Pubmed]
  16. Probing the importance of hydrogen bonds in the active site of the subtilisin nattokinase by site-directed mutagenesis and molecular dynamics simulation. Zheng, Z.L., Ye, M.Q., Zuo, Z.Y., Liu, Z.G., Tai, K.C., Zou, G.L. Biochem. J. (2006) [Pubmed]
  17. DNA topoisomerase I and PC4 can interact with human TFIIIC to promote both accurate termination and transcription reinitiation by RNA polymerase III. Wang, Z., Roeder, R.G. Mol. Cell (1998) [Pubmed]
  18. Positive Cofactor 4 (PC4) is critical for DNA repair pathway re-routing in DT40 cells. Caldwell, R.B., Braselmann, H., Schoetz, U., Heuer, S., Scherthan, H., Zitzelsberger, H. Sci. Rep. (2016) [Pubmed]
  19. Coactivation by OCA-B: definition of critical regions and synergism with general cofactors. Luo, Y., Ge, H., Stevens, S., Xiao, H., Roeder, R.G. Mol. Cell. Biol. (1998) [Pubmed]
  20. Repression of human gamma-globin gene expression by a short isoform of the NF-E4 protein is associated with loss of NF-E2 and RNA polymerase II recruitment to the promoter. Zhao, Q., Zhou, W., Rank, G., Sutton, R., Wang, X., Cumming, H., Cerruti, L., Cunningham, J.M., Jane, S.M. Blood (2006) [Pubmed]
  21. Biochemical characterization of the NF-Y transcription factor complex during B lymphocyte development. Currie, R.A. J. Biol. Chem. (1998) [Pubmed]
  22. Growth factor regulation of PC4/TIS7, an immediate early gene expressed during gut adaptation after resection. Swietlicki, E., Iordanov, H., Fritsch, C., Yi, L., Levin, M.S., Rubin, D.C. JPEN. Journal of parenteral and enteral nutrition. (2003) [Pubmed]
  23. Functional characterization of core promoter elements: DPE-specific transcription requires the protein kinase CK2 and the PC4 coactivator. Lewis, B.A., Sims, R.J., Lane, W.S., Reinberg, D. Mol. Cell (2005) [Pubmed]
  24. Effects of nicotinic acid on respiratory exchange ratio and substrate levels during exercise. Heath, E.M., Wilcox, A.R., Quinn, C.M. Medicine and science in sports and exercise. (1993) [Pubmed]
  25. Thyroid hormone receptor-associated proteins and general positive cofactors mediate thyroid hormone receptor function in the absence of the TATA box-binding protein-associated factors of TFIID. Fondell, J.D., Guermah, M., Malik, S., Roeder, R.G. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  26. p300-mediated acetylation of human transcriptional coactivator PC4 is inhibited by phosphorylation. Kumar, B.R., Swaminathan, V., Banerjee, S., Kundu, T.K. J. Biol. Chem. (2001) [Pubmed]
  27. Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development. Sakashita, K., Koike, K., Kinoshita, T., Shiohara, M., Kamijo, T., Taniguchi, S., Kubota, T. J. Clin. Invest. (2001) [Pubmed]
  28. Potential targets for HSF1 within the preinitiation complex. Yuan, C.X., Gurley, W.B. Cell Stress Chaperones (2000) [Pubmed]
  29. The coactivator p15 (PC4) initiates transcriptional activation during TFIIA-TFIID-promoter complex formation. Kaiser, K., Stelzer, G., Meisterernst, M. EMBO J. (1995) [Pubmed]
  30. Methylation of INK4 and CIP/KIP families of cyclin-dependent kinase inhibitor in chronic lymphocytic leukaemia in Chinese patients. Chim, C.S., Fung, T.K., Wong, K.F., Lau, J.S., Law, M., Liang, R. J. Clin. Pathol. (2006) [Pubmed]
  31. General transcriptional coactivator PC4 activates p53 function. Banerjee, S., Kumar, B.R., Kundu, T.K. Mol. Cell. Biol. (2004) [Pubmed]
  32. The intrinsically unstructured domain of PC4 modulates the activity of the structured core through inter- and intramolecular interactions. Jonker, H.R., Wechselberger, R.W., Boelens, R., Kaptein, R., Folkers, G.E. Biochemistry (2006) [Pubmed]
  33. Development of virus non-producer lymphosarcomas in pet cats exposed to FeLv. Hardy, W.D., McClelland, A.J., Zuckerman, E.E., Snyder, H.W., MacEwen, E.G., Francis, D., Essex, M. Nature (1980) [Pubmed]
  34. Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Wong, I.H., Ng, M.H., Huang, D.P., Lee, J.C. Blood (2000) [Pubmed]
  35. Spectrum of natural antibodies against five HTLV-III antigens in infected individuals: correlation of antibody prevalence with clinical status. Franchini, G., Robert-Guroff, M., Aldovini, A., Kan, N.C., Wong-Staal, F. Blood (1987) [Pubmed]
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