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  • Ifenprodil Tartrate The importance of G S phase progression

    2020-03-23

    The importance of G1–S phase progression to the formation of malignant tumors has been highlighted by the high incidence of aberrations in the genes involved in this progression in a wide variety of tumors. p27Kip1 is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors (CKI). Its role is to bind to and inhibit cyclin/cyclin-dependent kinase complexes, thereby negatively regulating Ifenprodil Tartrate progression. Numerous studies have shown that p27Kip1 is a tumor suppressor gene, the loss of which in tandem with mutations in several oncogenes and tumor suppressor genes facilitates tumor growth [3]. p27Kip1 is predominantly regulated by posttranslational modifications (primarily phosphorylation), which determine protein stability and subcellular localization [4]. Some controversy also exists regarding the importance of the cytoplasmic expression of p27Kip1, which was originally thought to represent a mechanism for inactivating p27Kip1 by sequestering it away from its site of action within the nucleus [5]. The quantity and function of p27Kip1 are regulated by changes in its protein levels and localization in the cell. In quiescent cells, p27Kip1 turnover is dependent upon its dephosphorylation at Ser10 and its interaction with cyclin-CDK complexes. However, the enzyme that mediates this degradation remains elusive [6]. Several laboratories have either reported that the cytoplasmic localization of p27Kip1 promoted its oncogenic activity or that p27Kip1 nuclear sequestration inhibited tumorigenesis. Akt-, ERK2-, CDK5- or hKIS-mediated p27Kip1 phosphorylation at Ser10 promotes CRM1-mediated nuclear export [7]. The human nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 (CRM1) is the major mammalian export protein that facilitates the transport of large macromolecules, including RNA and proteins, across the nuclear membrane to the cytoplasm [8]. This pleiotropic effect results from the now well-established function of CRM1 as a major nuclear export factor and/or from additional functions of CRM1 during mitosis [9]. Selective inhibitors of CRM1 may provide therapeutic benefits for patients with renal cell carcinomas [10]. CRM1 is responsible for transporting proteins that contain a nuclear export sequence, including p21 and the tumor suppressor p53, from the nucleus into the cytosol. p27Kip1 does not have a nuclear export sequence in its mRNA sequence, but Jab1 does. When p27Kip1 is phosphorylated at Ser10, it can be combined with Jab1 to form a complex that can penetrate from the nucleus to the cytoplasm by recruiting CRM1 [11]. In the present study, we investigated pSer10p27 and CRM1 expression in a series of 64 paraffin wax-embedded EOC tumor specimens using immunohistochemical staining. We then examined the correlations between the amounts of these proteins and various clinical and pathological features. We used gene overexpression and knockdown approaches to evaluate the precise roles of p27Kip1 and CRM1, respectively, in the SKOV3 EOC cell line. The results indicated that CRM1 knockdown and the induction of p27Kip1 expression are associated with decreased cancer cell proliferation and may be related to EOC progression.
    Materials and methods
    Results
    Discussion In the present study, we investigated the expression of the human CRM1 and pSer10p27 proteins in EOC tissues. Alterations in the protein expression of CRM1 and pSer10p27 may also affect tumor development; increased CRM1 and pSer10p27 protein expression may enhance malignancy. Our immunohistochemical staining results revealed that the expression of CRM1 and pSer10p27 was greatly increased (0.05) in grade III tumors as compared to grade I tumors (Fig. 1). There was a positive correlation between CRM1 and pSer10p27 expression (0.05, Fig. 2). Patients with increased CRM1 and pSer10p27 expression displayed reduced progression-free and overall survival rates (Fig. 3). These findings are consistent with those of a previous study [13].