[Frontiers in Bioscience 2, a26-30, September 15, 1997]
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CAVEAT LECTOR




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SPERMINE STIMULATES THE PHOSPHORYLATION OF THE NUCLEAR MATRIX PROTEINS CATALYZED BY NUCLEAR KINASE II

Rati Verma and Kuang Yu Chen

Department of Chemistry and The Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08855-0939

Received 8/19/97 Accepted 8/25/97

2. INTRODUCTION

NII Nuclear kinase is casein kinase 2 (CK2) present in the nucleus. Casein kinase 2 is a a second messenger-independent, multifunctional protein kinase capable of using acidic proteins such as phosvitin and casein as substrates but unable to phosphorylate basic proteins such as histones and protamines (1). The nuclear localization and the ubiquitous presence of NII nuclear kinase in eukaryotes, from yeast to mammalian cells, suggest that this enzyme may have important physiological functions. Although little is known about the regulation and function of CK2, studies from many laboratories have suggested that it may have an important role in regulating transcription and mitosis (2).

NII kinase has been shown to phosphorylate many important growth-related proteins such as c-fos (3) , p53 (4), and other transcription factors (2). CK2 consists of an alpha-catalytic subunit (Mr 35K-44K), and beta-regulatory subunit (Mr 25K-28K) arranged as an alpha2beta2 heterotetramer (5). Since the enzyme appears constitutively expressed, it has been difficult to determine whether and how the enzyme activity is regulated in vivo. Nevertheless, it has been shown that the CK2 activity is required for progression of the cell cycle (6, 7), suggesting that the enzyme activity is regulated during cell growth. One mechanism of regulation is through the presence of small positive or negative effectors. A number of inhibitors of NII nuclear kinase have been identified, including heparin, 2,3-biphosphoglycerate, inositol hexasulfate, and poly(U) (1). The physiological relevance of these inhibitors, however, has yet to be established. Other studies have shown that polyamines, particularly spermine, stimulate the phosphorylation of casein catalyzed by NII kinase (8). Polyamines (putrescine, spermidine, and spermine) are naturally occurring organic cations widely distributed in living organisms (9, 10). Studies from many laboratories have indicated that polyamines are essential for growth and play an important regulatory role in various biological processes (9-11). Thus, it is possible that polyamines may serve as a physiological effector of NII kinase. This notion is particularly tempting in view of the abundance of spermine in the nucleus (12) and possible role of nuclear protein phosphorylation in regulating gene expressions (2).

We have previously reported that spermine at physiological concentrations has a dual effect on the endogenous protein phosphorylation pattern of nuclei isolated from NB-15 mouse neuroblastoma cells. Spermine stimulates general nuclear protein phosphorylation but strongly inhibits the phosphorylation of two low molecular weight nuclear proteins, the 11,000- and 10,000- dalton proteins (13). We subsequently showed that the 11,000- and 10,000- dalton proteins are exclusive substrates of NI kinase, and spermine specifically inhibits the NI catalyzed phosphorylation (14). In this paper, we show that the stimulatory effect of spermine on the phosphorylation of other nuclear proteins is mediated with NII nuclear kinase. We also provide evidence that the stimulatory effect of spermine in nuclear protein phosphorylation is largely confined to nuclear matrix proteins.