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

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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


Nuclear protein kinase NI and NII are both ubiquitously present in eukaryotes and their activities appear to be independent of the regulation by any known second messengers (1, 2). Both enzymes are known to be able to phosphorylate casein, phosvitin but not histones (1). Although both enzymes appear to be abundantly localized in the nuclei, their precise physiological functions are not clear. The identification of their native substrate proteins and the search for their physiological effector(s) should facilitate our understanding of the physiological roles of these two enzymes.

In the present study, we showed that NII nuclear kinase could phosphorylate proteins in HMG, hnRNP and nuclear matrix (Figures 2-4), and appeared to have a broader substrate spectrum than that of NI kinase (14). The effects of spermine on the phosphorylation of these three subnuclear fractions, however, were very different. Thus, spermine only stimulated the NII kinase-catalyzed phosphorylation of nuclear matrix proteins, and had little or no effect when other subnuclear fractions were used as substrates. We have previously shown that spermine specifically inhibits the phosphorylation of the 11,000- and 10,000-dalton proteins catalyzed by NI kinase. It is of interest to note that these two low molecular weight proteins also exist in nuclear matrix fraction. The nuclear matrix has been shown to be the site of DNA replication (21, 22). Phosphorylation and dephosphorylation of nuclear matrix proteins could affect their binding to double-stranded or single stranded DNA (22). The fact that the specific and opposing effects of spermine on the actions of NI and NII kinase are localized only on nuclear matrix proteins may not be coincidental.

The finding that polyanions such as DNA, poly (U) and poly (A) could affect NII kinase catalyzed reactions, offers an interesting possibility that DNA and/or RNA may affect the phosphorylation status of their own binding proteins through their interaction with NII kinase. The difference in the inhibitory effects between poly (A) and poly (U) and the observation that spermine could reverse the inhibitory action of poly (A), and calf-thymus DNA, but not poly (U) also suggested that the inhibitory actions of these polyanions were not merely due to their negative charges.

In summary, many other protein kinases are regulated by various effectors such as cAMP, cGMP, and Ca2+. In view of the abundance of spermine in nucleus (9, 13), its diverse physiological effects in vitro and in vivo, and its specific but opposing effects on NI and NII kinase, it is tempting to propose that spermine may serve as the physiological modulator for both NI and NII kinases.