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Downregulation of the KIP family members p27 KIP1 and p57 KIP2 by SKP2 and the role of methylation in p57 KIP2 inactivation in nonsmall cell lung cancer
Author(s) -
Pateras Ioannis S.,
Apostolopoulou Kalliopi,
Koutsami Marilena,
Evangelou Kostas,
Tsantoulis Petros,
Liloglou Triantafillos,
Nikolaidis Giorgos,
Sigala Fragiska,
Kittas Christos,
Field John K.,
Kotsinas Athanassios,
Gorgoulis Vassilis G.
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22214
Subject(s) - cancer research , cell cycle , skp2 , cell growth , biology , downregulation and upregulation , methylation , kinase , cell , microbiology and biotechnology , ubiquitin , ubiquitin ligase , biochemistry , gene
Knowing the status of molecules involved in cell cycle control in cancer is vital for therapeutic approaches aiming at their restoration. The p27 KIP1 and p57 KIP2 cyclin‐dependent kinase inhibitors are nodal factors controlling normal cell cycle. Their expression in normal lung raises the question whether they have a mutual exclusive or redundant role in nonsmall cell lung cancer (NSCLC). A comparative comprehensive analysis was performed in a series of 70 NSCLCs. The majority of cases showed significantly reduced expression of both members compared to normal counterparts. Low KIP protein levels correlated with increased proliferation, which seems to be histological subtype preponderant. At mechanistic level, degradation by SKP2 was demonstrated, in vivo and in vitro , by siRNA‐methodology, to be the most important downregulating mechanism of both KIPs in NSCLC. Decreased p 57 KIP 2 ‐transcription complements the above procedure in lowering p57 KIP2 ‐protein levels. Methylation was the main cause of decreased p 57 KIP 2 ‐mRNA levels. Allelic loss and imprinting from LIT 1 mRNA contribute also to decreased p57 KIP2 transcription. In vitro recapitulation of the in vivo findings, in A549 lung cells ( INK 4A‐B (−/−) ), suggested that inhibition of the SKP2‐degradation mechanism restores p27 KIP1 and p57 KIP2 expression. Double siRNA treatments demonstrated that each KIP is independently capable of restraining cell growth. An additional demethylation step is required for complete reconstitution of p57 KIP2 expression in NSCLC. © 2006 Wiley‐Liss, Inc.