ABSTRACT
Also recent data strongly suggest the significance of cell cycle and its regula tors (cyclins, cyclin-dependent kinases (CD Ks), and their inhibitors), apoptosis and its inhibitors and their param ount significance for cancer therapy and devel opm ent of novel anticancer drugs (1-4). H ence, both cell cycle and apoptosis becam e potential targets for cancer treatm ent and design of new anticancer drugs. Since cancer cells differ from norm al cells in m any im portant characteris tics, including loss of differentiation, increased invasiveness and decreased drug sensitivity, and m ore recently the alterations in the critical regulatory proteins as a frequent defect in cancer cells. Thus these abnorm al m etabolic proteins, result ed from an enhanced "p roteo lysis" in cancer cells are p laying key regulatory roles in cell cycle, apoptosis, cell necrosis, and consequently a close interrelation betw een cancer cell m etabolism and fundam ental cell processes including cell cycle and apoptosis becam e the focus of several biochem ical, genetic and m olec ular studies, and the num ber of publications in this field dram atically increased in the last decade. Clearly, the balance o f protein concentrations, and the role of these "protein actives" is critical to the hom eostatic m echanism s of cancer cells (5 -7). A lthough, m ost o f the previous investigations indicated that the cell cycle is regulated m ainly by the w ell-tim ed production of regulatory proteins and their key role in controlling cell cycle, cell proliferation and tum or suppression by the n u cleocy top lasm ic tran sp ort and recen tly d iscovered in p ortin -a lp h a and
im portin-beta proteins w hich prom ote the transport of proteins into the nucleus as w ell as out of the nucleus back to the cytoplasm to prom ote new rounds of im port (or pendulin proteins) (5, 7). Recently a new protein term ed CAS (for cellular apoptosis susceptibility), a m am m alian m em ber of the im port in-beta pro teins w hich is m ay be im portant for translocation into the nucleus of som e com ponent of the tum or necrosis factor (TNF) activated signal transduction pathway. Thus different im portin-beta proteins m ay carry different classes of proteins and RN As both in and out of the nucleus, and the loss of function of different fam ily m em bers could result in different cell phenotypes. For instance, loss of CAS func tion appears to render cells resistant to apoptosis, while loss of transport of APC (anaphase prom oting com plex) m ay enhance the tendency to undergo apoptosis (7, 8).
