Journal Article

p27 Kip1 and Tumors: Characterization of CDKN1B Variants Identified in MEN4 and Breast Cancer

Parente, Daniela, Ali, Waqar, Bencivenga, Debora, Borriello, Adriana, Della Ragione, Fulvio, Azhar, Jahanzaib, Stampone, Emanuela, Del Vecchio, Vitale

2025

Overview

p27 is a key cell cycle gatekeeper governing the timing of Cyclin-dependent kinase (CDK) activation/inactivation and, consequently, cell proliferation. Structurally, the protein is largely unfolded, a feature that strongly increases its plasticity and interactors and enhances the number of regulated cellular processes. p27 , like other intrinsically unstructured proteins, is post-translationally modified on several residues. These modifications affect its cellular localization and address p27 for specific interactions/functions. Several germline or somatic (the p27 encoding gene) mutations have been demonstrated to be associated with multiple endocrine neoplasia type 4 (MEN4), hairy cell leukemia, small-intestine neuroendocrine tumors, and breast and prostate cancers. Here, we analyzed the effect of four missense and nonsense mutations found in patients affected by MEN4 or cancers, namely, c.349C>T, p.P117S; c.397C>A, p.P133T; c.487C>T, p.Q163*; and c.511G>T, p.E171*. By transfecting breast cancer cell lines, we observed increased growth and cell motility for all the investigated mutants compared to wild-type p27 transfected cells. Furthermore, we discovered that the mutant forms exhibited altered phosphorylation on key residues and different localization or degradation mechanisms in comparison to the wild-type protein and suggested a possible region as crucial for the lysosome-dependent degradation of the protein. Finally, the loss of p27 ability in blocking cell proliferation was in part explained through the different binding efficiency that mutant p27 forms exhibited with Cyclin/Cyclin-dependent Kinase complexes (or proteins involved indirectly in that binding) with respect to the WT.

• Subject: Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cell Line, Tumor / Cell Movement - genetics / Cell Proliferation - genetics / Cyclin-Dependent Kinase Inhibitor p27 - chemistry / Cyclin-Dependent Kinase Inhibitor p27 - genetics / Cyclin-Dependent Kinase Inhibitor p27 - metabolism / Female / Humans / Male / Mutation - genetics