Cooperative role between p21cip1/waf1 and p27kip1 in premature senescence in glandular proliferative lesions in mice.
Cellular senescence has been considered a novel target for cancer therapy. It has also been pointed out that p21(cip1/waf1) and p27(kip1) cyclin-dependent kinase inhibitors (CKIs) play a role in cellular senescence in some tumor types. Therefore, in order to address the possibility of a cooperative role between p21 and p27 proteins in senescence in vivo we analyzed cellular senescence in spontaneous glandular proliferative lesions (adrenal, thyroid and pituitary glands) in a double-KO mice model, using γH2AX, p53, p16, PTEN and Ki67 as senescence markers. The results obtained showed that p21p27 double-null mice had the lowest number of γH2AX positive cells in glandular hyperplasias and benign tumors. Also, in this group, Ki67 proliferation index correlated with a lower immunohistochemical expression of γH2AX and p53. The expression of p16 and PTEN do not seem to cause synergism of senescence in the benign lesions analyzed in p21p27 double-KO mice. These observations suggest an intrinsic cooperation between p21 and p27 CKIs in the activation of stress-induced cellular senescence and tumor progression in vivo, which would be a physiological mechanism to prevent tumor cell proliferation.
Departamento de Medicina y Cirugía Animal, Facultad Veterinaria, UCM, Madrid, Spain.
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García-Fernández
Departamento de Medicina y Cirugía Animal, Facultad Veterinaria, UCM, Madrid, Spain.
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García-Palencia
Departamento de Medicina y Cirugía Animal, Facultad Veterinaria, UCM, Madrid, Spain.
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Suarez
Departamento de Medicina y Cirugía Animal, Facultad Veterinaria, UCM, Madrid, Spain.
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Sánchez
IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
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Gil-Gómez
Departamento de Medicina y Cirugía Animal, Facultad Veterinaria, UCM, Madrid, Spain.
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Sánchez
Departamento de Medicina y Cirugía Animal, Facultad Veterinaria, UCM, Madrid, Spain.
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Rollán
Parc de Recerca Biomèdica de Barcelona, Barcelona. Spain.
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Martín-Caballero
Departamento de Medicina y Cirugía Animal, Facultad Veterinaria, UCM, Madrid, Spain. jflores@ucm.es.
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Flores
D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005260:Female; D006965:Hyperplasia / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27