Disease relevance of PCSK4

• Thus, abnormal processing of IGF-II by PC4 may represent a previously uncharacterized mechanism involved in the pathophysiology of fetoplacental growth restriction, and elevated pro-IGF-II may be a useful clinical marker for risk of IUGR [1].

High impact information on PCSK4

• The inhibitory activity is attenuated on bona fide promoters by (i) transcription factor TFIIH and (ii) phosphorylation of PC4 [2].
• PC4 is a nuclear DNA-binding protein that stimulates activator-dependent class II gene transcription in vitro [2].
• We have analyzed the mechanisms underlying stimulation of transcription by the activator GAL4-AH and the recombinant coactivator p15 (PC4) [3].
• PC4 is predominantly associated with the chromatin throughout the stages of cell cycle and is broadly distributed on the mitotic chromosome arms in a punctate manner except for the centromere [4].
• Silencing of PC4 expression in HeLa cells results in chromatin decompaction, as evidenced by the increase in MNase accessibility [4].

Biological context of PCSK4

• Knocking down of PC4 up-regulates several genes, leading to the G(2)/M checkpoint arrest of cell cycle, which suggests its physiological role as a chromatin-compacting protein [4].
• In this simplified model for gene activation VP16 recruits the general factors and the cofactors Mediator, GCN5, CBP, and PC4, within minutes to the promoter region [5].

Anatomical context of PCSK4

• Moreover, P3CSK4 and P2CSK4, but neither the mono-palmitoylated PCSK4 analog nor the CSK4 peptide, increased the frequency of IFN-gamma-producing T cells expanded under similar conditions [6].

Associations of PCSK4 with chemical compounds

• Sarkosyl disruption of preinitiation complex formation further illustrates that PC4 can only inhibit transcription prior to the assembly of a functional preinitiation complex [7].
• For phenol and 1-naphthol, the largest K(oc) values occurred in PC4 with polar aromatic cores: approximattely 17 and approximately 7 times higher than the respective K(owc), suggesting that PC4 was much more accessible and compatible to polar aromatic pollutants than nonpolar aromatic pollutants [8].
• We propose a model for co-ordinated changes in PC4 cofactor functions, mediated by phosphorylation status-dependent gradual masking of the lysine-rich region causing shielding or exposure of interaction surfaces [9].

Other interactions of PCSK4

• Multiple transcripts are produced for all the mammalian convertases, but only in the cases of PC4, PACE4, and PC5 does differential splicing result in the modification of the C-terminal sequence of these enzymes [10].
• The conclusions drawn from the results of this study may well be applicable to the mammalian convertases PC4, PACE4, and PC5, which also display C-terminal sequence heterogeneity [10].
• In contrast, the integrity of the TLR2 holoprotein was compulsory for effective cellular recognition of other TLR2 agonists applied, including PCSK4 [11].
• Under limiting concentrations, PC2 and PC4 also show synergistic effects [12].
• The presence of TBP-associated factors, however, helps overcome PC4 repression and further enhance the level of activation mediated by TBP [7].

Analytical, diagnostic and therapeutic context of PCSK4

• The USA-derived coactivators PC2 and PC4 fully reconstitute the USA coactivator activity, both by repressing the basal level of transcription and by potentiating activator function to yield large increases in the levels of transcription induction [12].
• It selectively interacts with core histones H3 and H2B; this interaction is essential for PC4-mediated chromatin condensation, as demonstrated by micrococcal nuclease (MNase) accessibility assays, circular dichroism spectroscopy, and atomic force microscopy (AFM) [4].

References