Regulation of p27Kip1 and p57Kip2 Functions by Natural Polyphenols

Abstract

In numerous instances, the fate of a single cell not only represents its peculiar outcome but also contributes to the overall status of an organism. In turn, the cell division cycle and its control strongly influence cell destiny, playing a critical role in targeting it towards a specific phenotype. Several factors participate in the control of growth, and among them, p27^Kip1 and p57^Kip2, two proteins modulating various transitions of the cell cycle, appear to play key functions. In this review, the major features of p27 and p57 will be described, focusing, in particular, on their recently identified roles not directly correlated with cell cycle modulation. Then, their possible roles as molecular effectors of polyphenols' activities will be discussed. Polyphenols represent a large family of natural bioactive molecules that have been demonstrated to exhibit promising protective activities against several human diseases. Their use has also been proposed in association with classical therapies for improving their clinical effects and for diminishing their negative side activities. The importance of p27^Kip1 and p57^Kip2 in polyphenols' cellular effects will be discussed with the aim of identifying novel therapeutic strategies for the treatment of important human diseases, such as cancers, characterized by an altered control of growth.

Keywords: EGCG; p27Kip1; p57Kip2; polyphenols; resveratrol.

Figure 1

Domain structures of cyclin-dependent kinase (CDK) Interacting Protein (CIP)/Kinase Inhibitory Protein (Kip) proteins with the main post-translational modifications (PTMs), putative kinases, and interactors of p27Kip1 and p57Kip2. Panel (A) Schematic representation of p21Cip1, p27Kip1, and p57Kip2 protein domain structures. The three siblings share a highly conserved N-terminal domain called the Kinase Inhibitory Domain (KID) that includes the cyclin-binding domain (D1) and the CDK-binding domain (D2) connected by a linker helix (LH). The Oxygen-Dependent Degradation Domain (ODD), reported for the binding of Von Hippel Lidau (VHL), partially overlaps with the D1 domain. NES (Nuclear Export Signal); NLS (Nuclear Localization Signal). Panel (B) Known PTMs, kinases, and interactors of p27 and p57. In the panel, the domain structures of p27 and p57 are reported. The main sites of phosphorylation for both the proteins are indicated with spots along the sequence. At the site of the phosphorylation, the putative kinases responsible for the phosphorylations are also indicated. One acetylated site is reported for p27 (K100), and it is indicated on the protein with a triangle. The interactors of the two proteins, mentioned and described in the text, are also reported in correspondence with their binding site.

Figure 2

Schematic representation of the main roles of p27^Kip1 and p57^Kip2. In the nucleus, both the proteins are key modulators of the cyclin/CDK complexes, mainly inhibiting their activities and preventing cell cycle progression. In the case of phosphorylation on Tyrosine 74 of p27, this protein turns into an activator of the complex CDK4/cyclin D1, promoting cell cycle progression. In addition, p27 and p57 can take part in transcription factor complexes to promote or to inhibit gene expression during development, cell differentiation, and cell cycle progression. The main interactors are reported in correspondence with each protein complex on DNA. In the cytoplasm, the proteins can be involved in the regulation of several processes such as apoptosis, responses to several stressors, and cytoskeletal dynamics during mitosis, tumor cell invasion, and metastasis. aa (amino acids). Cyt. c (Cytochrome c). Refer to Section 2.1.1 and Section 2.2.1 for a detailed description of the activities of p27 and p57 represented in this figure.

Figure 3

Schematic representation of selected polyphenols that interfere with p27 expression and activity (see Table 1 and text for details). Epigallocatechin-3-gallate (EGCG) increases the expression of p27, acting at multiple levels: stimulating the activity of its transcription factors (TFs, mainly FoxO) or inhibiting its proteasomal degradation. Resveratrol inhibits the pathway (PI₃K/AKT) that negatively regulates the transcription of the CDK1B gene. Tannins also act by directly binding and inhibiting the proteasome-dependent degradation of p27. Acteoside increases CDK1B mRNA synthesis and favors the binding of p27 to CDK4/6, contributing to the reduction of their kinase activity. The increased expression of p27 potentiates its inhibitory effect on cell cycle progression, blocking malignant cells at the G1/S transition. Dashed red and green arrows indicate inhibition and activation, respectively, mediated by “indirect” interactions between the indicated polyphenols and p27-regulating factors.

Figure 4

Schematic representation of how selected polyphenols can interact with p57 expression and activity (see Table 1 and text for details). EGCG, as well as other catechins, upregulates the expression of p57 in normal cells, inducing differentiation (e.g., human keratinocytes), acting on CDKN1C gene transcription via members of the MAPK family, possibly p38. In cancer cells, the increased expression of p57 leads to apoptosis through a pathway probably involving JNK. Quercetin also induces apoptosis, upregulating CDKN1C gene expression via uncharacterized factors. Dashed green arrows indicate activation mediated by “indirect” interactions between the indicated polyphenols and p57-regulating factors.