Cyclin-dependent kinase inhibitors (CKIs) and hematological malignancies

Abstract

Cell proliferation control is ensured by a group of proteins named cyclin-dependent kinases (CDKs), the activation of which is dependent on phosphorylation and cyclin association. In parallel, these CDKs are negatively controlled by two distinct groups of inhibitory proteins, the cyclin-dependent kinase inhibitors (CKIs). The first group, including p16Ink4a, p15Ink4b, p18Ink4c and p19Ink4d, is specific for the G1 CDKs, CDK4 and CDK6, inhibiting the kinase activity of cyclin D/CDK4-CDK6 complexes on pRb. p16Ink4a, down-regulated by pRb, inhibits G1 CDKs by competition with cyclin D; p15Ink4b, the synthesis of which is induced by TGF beta, seems to be a mediator of TGF beta-mediated cell cycle arrest. Furthermore, p18Ink4c inhibits CDK6 phosphorylation and activation by CAK. The second CKIs family is constituted by p21Waf1, p27Kip1 and p57Kip2. Their inhibitory action concerns a large range of cyclin/CDK complexes involved in G1 and S phase. p21Waf1, induced in part by p53, is up-regulated by senescence, DNA damage and cellular differentiation. p21Waf1 forms quaternary complexes with CDKs, cyclins and PCNA. Its inhibitory action, preventing CDK from phosphorylation, depends on the stoichiometry of the components. As p15Ink4b, p27Kip1 causes late G1 cell cycle arrest after TGF beta treatment and contact inhibition. The implications of CKIs in hematological malignancies are function of deletions or mutations of their genes. p16Ink4a and p15Ink4b genes, localized on 9p21, present frequent homozygous deletions in ALL T, ATL and lymphoblastic acutisation of CML. The other CKIs present very rare homozygous deletions or mutations, particularly p21Waf1 and p27Kip2. However, reduction of inhibitory activity due to hemizygous deletions might favour leukemogenesis.

Combination of SK-7041, one of novel histone deacetylase inhibitors, and STI571-induced synergistic apoptosis in chronic myeloid leukemia

“…Increasing p21 CIP1 = WAF1 expression could affect the phosphorylation of CDK4. The blocking at G 1 from entry into the S-phase appears to be mediated by the downregulation of the CDK4-associated kinase activity in association with the induction of p21 CIP1 = WAF1 [13,14]. With combined treatment in our experiment, the expression levels of cyclin D1 and CDK4 were lower when compared with either treatment alone.…”

Down-regulation of Human DNA-(Cytosine-5) Methyltransferase Induces Cell Cycle Regulators p16 and p21WAF/Cip1 by Distinct Mechanisms

“…Rapid Induction of p21 WAF1 by DNA MeTase InhibitionAnother member of the cyclin-dependent kinase inhibitor (CDKI) family p21 WAF1 , inhibits a wide range of cyclin⅐CDK complexes involved in G 1 and S phase progression (43)(44)(45). Recently it has been observed that an inverse correlation exists between p21 WAF1 and DNA MeTase protein levels in SV40-transformed and nontransformed cells (46).…”

Secalonic acid D blocks embryonic palatal mesenchymal cell‐cycle by altering the activity of CDK2 and the expression of p21 and cyclin E

“…The reduction in the activity of CDK4, 6 and 2 by SAD in HEPM cell cultures ( in vitro ) and of CDK 2 in vivo can also be a consequence of SAD‐induced increase in the levels of the CDK inhibitors including p21 and p57 in vitro and possibly p21 in vivo. Increased levels of p21 are known to inhibit CDK kinase activity (Baghdassarian and Ffrench, 1996). Another mechanism by which SAD‐induced increase in the p21 level can contribute to the anti‐proliferative activity of SAD is by its binding to PCNA leading to inhibition of its function in DNA replication (Helt and Galloway, 2003).…”