Cell cycle regulation by the intrinsically disordered proteins p21 and p27

Abstract

Today, it is widely accepted that proteins that lack highly defined globular three-dimensional structures, termed IDPs (intrinsically disordered proteins), play key roles in myriad biological processes. Our understanding of how intrinsic disorder mediates biological function is, however, incomplete. In the present paper, we review disorder-mediated cell cycle regulation by two intrinsically disordered proteins, p21 and p27. A structural adaptation mechanism involving a stretchable dynamic linker helix allows p21 to promiscuously recognize the various Cdk (cyclin-dependent kinase)-cyclin complexes that regulate cell division. Disorder within p27 mediates transmission of an N-terminal tyrosine phosphorylation signal to a C-terminal threonine phosphorylation, constituting a signalling conduit. These mechanisms are mediated by folding upon binding p21/p27's regulatory targets. However, residual disorder within the bound state contributes critically to these functional mechanisms. Our studies provide insights into how intrinsic protein disorder mediates regulatory processes and opportunities for designing drugs that target cancer-associated IDPs.

Targeting unfolded protein response in cancer and diabetes

“…A pro-survival function of p21 in b-cells which was analogous to that demonstrated previously in the context of carcinogenesis (Yoon et al 2012) was confirmed in the pancreatic islets isolated from the w/t and p21 KO mice. The latter were found significantly more sensitive to high glucose levels with a characteristic increase in caspase activation -a clear indication of ongoing apoptosis.…”

“…For instance, it is known that p21 may act not only as a tumor suppressor but also serve as an oncogene by promoting cell growth and inhibiting apoptosis (Yoon et al 2012). Such an oncogenic function is thought to be associated with the cytoplasmic localization of p21 (Zhou et al 2001).…”

“…In addition to p21, another member of the CIP/KIP family of cyclin-dependent kinase inhibitor proteins, p27, is similarly active in suppressing cell proliferation (Yoon et al 2012). Is it another downstream target of CHOP and thus, is it involved in the pro-apoptotic branch of UPR?…”

Histone Deacetylase Inhibitors: An Attractive Therapeutic Strategy Against Breast Cancer

“…In addition, levels of p21 (cyclin-dependent kinase inhibitor 1 (WAF1)) and p27 (kinesin-like protein (KIP1)) proteins increased, as did apoptosis regulator BCL-2-like protein 4 (BAX) expression, whereas apoptosis regulator B-cell lymphoma 2 (BCL2) expression was reduced (69). p21 and p27 are inhibitors of cyclin-dependent kinases, hence they are involved in cellcycle control (70) and appear to suppress MCG-7 cell proliferation in vitro (71). BAX is a pro-apoptotic member of the BCL2 family and a downstream target gene of p53 that mediates p53-dependent apoptosis (72).…”

Correlation between PDZK1, Cdc37, Akt and Breast Cancer Malignancy: The Role of PDZK1 in Cell Growth through Akt Stabilization by Increasing and Interacting with Cdc37

“…Perturbations in Akt activity are associated with numerous pathologies including breast cancer (11). Akt promotes a reduction of cell cycle inhibitors such as the cyclin-dependent kinase inhibitor 1 (p21/WAF1) and p27 Kip1 and an enhancement of cell cycle proteins such as c-Myc and cyclin D1 (12). PDZ domain containing 1 (PDZK1) is a 70-kDa adapter protein expressed primarily in the apical brush-border membrane of the proximal tubules of the kidney (13) and has an important role in lipid metabolism.…”