{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:01:33Z","timestamp":1792789293850,"version":"4.5.0"},"reference-count":96,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,26]],"date-time":"2025-01-26T00:00:00Z","timestamp":1737849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PON Ricerca e Innovazione 2014\u20132020","award":["11653"],"award-info":[{"award-number":["11653"]}]},{"name":"PON Ricerca e Innovazione 2014\u20132020","award":["(CUP:B63C22001470005 to E.S.)"],"award-info":[{"award-number":["(CUP:B63C22001470005 to E.S.)"]}]},{"name":"Bando di Ateneo per il finanziamento di progetti di ricerca fondamentale ed applicata dedicato ai giovani Ricercatori, Kip2PTMCaTR","award":["11653"],"award-info":[{"award-number":["11653"]}]},{"name":"Bando di Ateneo per il finanziamento di progetti di ricerca fondamentale ed applicata dedicato ai giovani Ricercatori, Kip2PTMCaTR","award":["(CUP:B63C22001470005 to E.S.)"],"award-info":[{"award-number":["(CUP:B63C22001470005 to E.S.)"]}]},{"name":"MUR, CN3 National Center for Gene Therapy and Drug Based on RNA Technology, Spoke 2.","award":["11653"],"award-info":[{"award-number":["11653"]}]},{"name":"MUR, CN3 National Center for Gene Therapy and Drug Based on RNA Technology, Spoke 2.","award":["(CUP:B63C22001470005 to E.S.)"],"award-info":[{"award-number":["(CUP:B63C22001470005 to E.S.)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>p27Kip1 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. p27Kip1, like other intrinsically unstructured proteins, is post-translationally modified on several residues. These modifications affect its cellular localization and address p27Kip1 for specific interactions\/functions. Several germline or somatic CDKN1B (the p27Kip1 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 CDKN1B missense and nonsense mutations found in patients affected by MEN4 or cancers, namely, c.349C&gt;T, p.P117S; c.397C&gt;A, p.P133T; c.487C&gt;T, p.Q163*; and c.511G&gt;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 p27Kip1 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 p27Kip1 ability in blocking cell proliferation was in part explained through the different binding efficiency that mutant p27Kip1 forms exhibited with Cyclin\/Cyclin-dependent Kinase complexes (or proteins involved indirectly in that binding) with respect to the WT.<\/jats:p>","DOI":"10.3390\/cells14030188","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T04:59:10Z","timestamp":1737953950000},"page":"188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["p27Kip1 and Tumors: Characterization of CDKN1B Variants Identified in MEN4 and Breast Cancer"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0977-5374","authenticated-orcid":false,"given":"Debora","family":"Bencivenga","sequence":"first","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cL. Vanvitelli\u201d, Via Luigi De Crecchio, 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5828-1739","authenticated-orcid":false,"given":"Emanuela","family":"Stampone","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cL. Vanvitelli\u201d, Via Luigi De Crecchio, 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jahanzaib","family":"Azhar","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cL. Vanvitelli\u201d, Via Luigi De Crecchio, 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Parente","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cL. Vanvitelli\u201d, Via Luigi De Crecchio, 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waqar","family":"Ali","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique, University of Montpellier, UMR9002, 141 rue de la Cardonille, 34396 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7323-4444","authenticated-orcid":false,"given":"Vitale","family":"Del Vecchio","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Section of Human Histology and Embryology, University of Campania \u201cL. Vanvitelli\u201d, Via L. Armanni 5, 80128 Naples, Italy"},{"name":"Department of Life Sciences, Health and Health Professions, Link Campus University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0592-4283","authenticated-orcid":false,"given":"Fulvio","family":"Della Ragione","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cL. Vanvitelli\u201d, Via Luigi De Crecchio, 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9026-8048","authenticated-orcid":false,"given":"Adriana","family":"Borriello","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cL. Vanvitelli\u201d, Via Luigi De Crecchio, 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7598","DOI":"10.1021\/bi8006803","article-title":"Regulation of cell division by intrinsically unstructured proteins: Intrinsic flexibility, modularity, and signaling conduits","volume":"47","author":"Galea","year":"2008","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bencivenga, D., Stampone, E., Roberti, D., Della Ragione, F., and Borriello, A. (2021). p27(Kip1), an Intrinsically Unstructured Protein with Scaffold Properties. Cells, 10.","DOI":"10.3390\/cells10092254"},{"key":"ref_3","first-page":"25","article-title":"Inhibitors of the Cip\/Kip family","volume":"227","author":"Hengst","year":"1998","journal-title":"Curr. Top. Microbiol. 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