Regulation of p53 mediated transactivation by the β‐subunit of protein kinase CK2

Abstract

The growth suppressor protein p53 plays a main part in cellular growth control. Two of its key functions are sequence specific DNA binding and transactivation. Functions of p53 in growth control are regulated at least in part by its interaction with protein kinases. p53 binds to protein kinase CK2, formerly known as casein kinase 2, and it is phosphorylated by this enzyme. CK2 is composed of two regulating L L-subunits and two catalytic K K-or K KP-subunits and the interaction with p53 is mediated by the regulatory L L-subunit of CK2. Recently we showed that the L L-subunit could inhibit the sequence specific DNA binding activity of p53 in vitro. Based on this finding, we asked if a coexpression of the L L-subunit of CK2 with p53 in mammalian cells could inhibit the DNA binding activity of p53 in a physiological context. We found that the coexpression of the L Lsubunit showed the same inhibitory effect as in the previous assays with purified proteins. Then, we investigated the effects of the coexpression of the L L-subunit of CK2 on the transactivation and transrepression activity of p53. We found that transactivation of the mdm2, p21 epIagsI and cyclin G promoter was inhibited in three different cell lines whereas transactivation of the bax promoter was not affected in COS1 cells but downregulated in MCO1 and SaosS138V21 cells. p53 mediated transrepression of the fos promoter was not influenced by coexpression of the CK2 L L-subunit. Taken together we propose a cell type dependent fine regulation of the p53 transactivation function by the CK2 L L-subunit in vivo, which does not affect p53 mediated transrepression.z 1999 Federation of European Biochemical Societies.

Inducible expression of the regulatory protein kinase CK2β subunit: Incorporation into complexes with catalytic CK2 subunits and re‐examination of the effects of CK2β on cell proliferation

“…In vertebrates, the CK2 regulatory subunit is also suggested to participate in cell cycle progression, cellular proliferation, as well as radiation-induced DNA damage signaling [Lorenz et al, 1993;Toczyski et al, 1997;Li et al, 1999]. At the molecular level, free CK2b can interact with the p53 tumor suppressor and is presumed to direct some of its cellular processes [Filhol et al, 1992;Appel et al, 1995;Gotz et al, 1996;Prowald et al, 1997;Schuster et al, 1999]. Other CK2b-interacting proteins that appear to interact with CK2b in the absence of catalytic CK2 subunits include A-Raf and c-Mos [Boldyreff and Issinger, 1997;Hagemann et al, 1997;Li et al, 1997].…”

“…The catalytic isozymes are responsible for serine/threonine phosphorylation of CK2 targets while the regulatory CK2b has a number of modulatory functions associated with the stability, activity, and speci®city of CK2a and CK2a' in the holoenzyme complex . Evidence also strongly suggests that CK2b has functions independent of the CK2 tetramer complex through its interaction with numerous cytoplasmic and nuclear cellular proteins such as CD5 [Raman et al, 1998], c-Mos , Nopp140 , A-Raf [Boldyreff and Issinger, 1997;Hagemann et al, 1997], p21 [Gotz et al, 1996], and p53 [Filhol et al, 1992;Appel et al, 1995;Prowald et al, 1997;Schuster et al, 1999].…”

Significance of protein kinase CK2 nuclear signaling in neoplasia

“…Of note are the observations that the gene for protein B23 (a substrate for CK2, as discussed above) is involved in two chromosomal translocations that are seen in anaplastic large cell lymphoma, childhood acute myeloid leukemia, and acute promyelocytic leukemia [for review see, e.g., Drexler et al, 2000]. Similar considerations pertain to the interaction of CK2 with the tumor suppressor gene product p53 for its functional activity in the nucleus under various conditions [Schuster et al, 1999].…”

Subcellular localization of protein kinase CK2

“…Moreover, there are now an increasing number of proteins binding exclusively to the catalytic α-or the regulatory β-subunit (Glover 1998;Guerra and Issinger 1999).These interactions can lead to an alteration of the enzymatic activity of the kinase itself (Götz et al 1996;Guerra et al 1997;N. Schuster, C. Götz, E. Schneider, A. Prowald, M. Faust, M. Montenarh, unpublished work), as well as of its binding partners such as the tumor suppressor p53, protein phosphatase 2A, and topoisomerase (Hériché et al 1997;Prowald et al 1997;Redwood et al 1998;Schuster et al 1999). Although the number of new, interacting partners of protein kinase CK2 is increasing rapidly, we are still in the early stages of understanding the regulation and the cellular function of this kinase.…”