p27<sup>Kip1</sup> and Tumors: Characterization of <i>CDKN1B</i> Variants Identified in MEN4 and Breast Cancer
p27<sup>Kip1</sup> 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 enhan...
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2025-01-01
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| author | Debora Bencivenga Emanuela Stampone Jahanzaib Azhar Daniela Parente Waqar Ali Vitale Del Vecchio Fulvio Della Ragione Adriana Borriello |
| author_facet | Debora Bencivenga Emanuela Stampone Jahanzaib Azhar Daniela Parente Waqar Ali Vitale Del Vecchio Fulvio Della Ragione Adriana Borriello |
| author_sort | Debora Bencivenga |
| collection | DOAJ |
| description | p27<sup>Kip1</sup> 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<sup>Kip1</sup>, like other intrinsically unstructured proteins, is post-translationally modified on several residues. These modifications affect its cellular localization and address p27<sup>Kip1</sup> for specific interactions/functions. Several germline or somatic <i>CDKN1B</i> (the p27<sup>Kip1</sup> 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 <i>CDKN1B</i> 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<sup>Kip1</sup> 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<sup>Kip1</sup> ability in blocking cell proliferation was in part explained through the different binding efficiency that mutant p27<sup>Kip1</sup> forms exhibited with Cyclin/Cyclin-dependent Kinase complexes (or proteins involved indirectly in that binding) with respect to the WT. |
| format | Article |
| id | doaj-art-ce321768167a4c97b970daa0b06c4e7f |
| institution | DOAJ |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-ce321768167a4c97b970daa0b06c4e7f2025-08-20T03:12:35ZengMDPI AGCells2073-44092025-01-0114318810.3390/cells14030188p27<sup>Kip1</sup> and Tumors: Characterization of <i>CDKN1B</i> Variants Identified in MEN4 and Breast CancerDebora Bencivenga0Emanuela Stampone1Jahanzaib Azhar2Daniela Parente3Waqar Ali4Vitale Del Vecchio5Fulvio Della Ragione6Adriana Borriello7Department of Precision Medicine, University of Campania “L. Vanvitelli”, Via Luigi De Crecchio, 7, 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “L. Vanvitelli”, Via Luigi De Crecchio, 7, 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “L. Vanvitelli”, Via Luigi De Crecchio, 7, 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “L. Vanvitelli”, Via Luigi De Crecchio, 7, 80138 Naples, ItalyCentre National de la Recherche Scientifique, University of Montpellier, UMR9002, 141 rue de la Cardonille, 34396 Montpellier, FranceDepartment of Experimental Medicine, Section of Human Histology and Embryology, University of Campania “L. Vanvitelli”, Via L. Armanni 5, 80128 Naples, ItalyDepartment of Precision Medicine, University of Campania “L. Vanvitelli”, Via Luigi De Crecchio, 7, 80138 Naples, ItalyDepartment of Precision Medicine, University of Campania “L. Vanvitelli”, Via Luigi De Crecchio, 7, 80138 Naples, Italyp27<sup>Kip1</sup> 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<sup>Kip1</sup>, like other intrinsically unstructured proteins, is post-translationally modified on several residues. These modifications affect its cellular localization and address p27<sup>Kip1</sup> for specific interactions/functions. Several germline or somatic <i>CDKN1B</i> (the p27<sup>Kip1</sup> 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 <i>CDKN1B</i> 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<sup>Kip1</sup> 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<sup>Kip1</sup> ability in blocking cell proliferation was in part explained through the different binding efficiency that mutant p27<sup>Kip1</sup> forms exhibited with Cyclin/Cyclin-dependent Kinase complexes (or proteins involved indirectly in that binding) with respect to the WT.https://www.mdpi.com/2073-4409/14/3/188p27<sup>Kip1</sup><i>CDKN1B</i>cell cyclecell motilitytumor suppressor genecancer |
| spellingShingle | Debora Bencivenga Emanuela Stampone Jahanzaib Azhar Daniela Parente Waqar Ali Vitale Del Vecchio Fulvio Della Ragione Adriana Borriello p27<sup>Kip1</sup> and Tumors: Characterization of <i>CDKN1B</i> Variants Identified in MEN4 and Breast Cancer Cells p27<sup>Kip1</sup> <i>CDKN1B</i> cell cycle cell motility tumor suppressor gene cancer |
| title | p27<sup>Kip1</sup> and Tumors: Characterization of <i>CDKN1B</i> Variants Identified in MEN4 and Breast Cancer |
| title_full | p27<sup>Kip1</sup> and Tumors: Characterization of <i>CDKN1B</i> Variants Identified in MEN4 and Breast Cancer |
| title_fullStr | p27<sup>Kip1</sup> and Tumors: Characterization of <i>CDKN1B</i> Variants Identified in MEN4 and Breast Cancer |
| title_full_unstemmed | p27<sup>Kip1</sup> and Tumors: Characterization of <i>CDKN1B</i> Variants Identified in MEN4 and Breast Cancer |
| title_short | p27<sup>Kip1</sup> and Tumors: Characterization of <i>CDKN1B</i> Variants Identified in MEN4 and Breast Cancer |
| title_sort | p27 sup kip1 sup and tumors characterization of i cdkn1b i variants identified in men4 and breast cancer |
| topic | p27<sup>Kip1</sup> <i>CDKN1B</i> cell cycle cell motility tumor suppressor gene cancer |
| url | https://www.mdpi.com/2073-4409/14/3/188 |
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