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Nuclear Protein Phosphorylation and the Regulation of Gene Expression

  • Chapter
Cyclic Nucleotides

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 58 / 1))

Overview

The involvement of cyclic AMP-dependent protein kinase in the phosphorylation of chromosomal proteins is well known. Perhaps the best examples of nuclear proteins phosphorylated by this enzyme are histone H 1 and certain non-histone proteins, each of which is phosphorylated in vivo in response to agents that raise levels of cyclic AMP. Histone H 1 from calf thymus is phosphorylated at serine residue 38, and peptide analogs of this site have been used in studies of catalysis by the C-subunit of the kinase in vitro. Kinetic analyses indicate that phosphorylation proceeds by a random sequential interaction of the enzyme with ATP and peptide substrates. The data do not rule out the presence of a transient phosphoenzyme intermediate in catalysis, but they do indicate the formation of a ternary complex between enzyme, Mg-ATP and peptide which may be significant in the design of active site-directed inhibitors. Studies on the location and translocation of kinase subunits suggest a complex regulatory role for this enzyme in the nucleus. One consequence of histone phosphorylation could be an alteration of nucleosome structure leading to changes in functional activities over broad regions of the chromatin. However, at this point no functional significance can be attributed to any site-specific nuclear protein phosphorylation.

Newly-developed methods should aid in clarifying functional roles of protein kinase substrates. One method involves the isolation of cell mutants deficient in different aspects of phosphorylation. These can be used to assess the importance of phosphorylation in various cellular processes. Another new method involves the use of 5′-[γ-S] ATP as a protein kinase substrate. The thiophosphate group serves as an affinity probe for isolation of newly-phosphorylated proteins. This procedure allows examination of activity of a phosphorylated protein separated from its non-phosphorylated counterparts.

Numerous phosphoproteins have been implicated in reactions related to gene expression both at transcriptional and translational levels. In many cases it is difficult to consider separately cyclic AMP-dependent and -independent phosphorylations with regard to their ultimate roles. For example, translation may involve multiple phosphorylation of ribosomal proteins, not all responsive to cyclic AMP. Phosphorylation occurs on both ribosomal subunit proteins and initiation factors.

Recently, peptides encoded by viral nucleic acids have been shown to possess protein kinase activity. The pp 60src protein specified by avian sarcoma virus is apparently a cyclic AMP-independent protein kinase. It is interesting that this protein is itself a phosphoprotein, and that phosphorylation at one site, a serine residue, is stimulated by cyclic AMP. These results point out the importance of protein phosphorylation to the process of cell transformation and emphasize the necessity for functional identification of protein kinase substrates.

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Authors
  1. E. M. Johnson
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  1. Neuropharmacology Research Laboratory, Departments of Neurology and Pharmacology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, 02114, USA

    J. A. Nathanson

  2. Biochemical Neuropharmacology Unit, NINCDS National Institutes of Health, Bethesda, MD, 20205, USA

    J. W. Kebabian

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© 1982 Springer-Verlag Berlin Heidelberg

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Johnson, E.M. (1982). Nuclear Protein Phosphorylation and the Regulation of Gene Expression. In: Nathanson, J.A., Kebabian, J.W. (eds) Cyclic Nucleotides. Handbook of Experimental Pharmacology, vol 58 / 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-68111-0_15

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  • DOI: https://doi.org/10.1007/978-3-642-68111-0_15

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