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Induction of p16 INK4A mediated by β‐catenin in a TCF4‐independent manner: Implications for alterations in p16 INK4A and pRb expression during trans ‐differentiation of endometrial carcinoma cells
Author(s) -
Saegusa Makoto,
Hashimura Miki,
Kuwata Takeshi,
Hamano Mieko,
Okayasu Isao
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.22112
Subject(s) - catenin , cyclin d1 , cancer research , retinoblastoma protein , biology , cell cycle , cell growth , phosphorylation , transcription factor , cyclin , cell , microbiology and biotechnology , medicine , gene , signal transduction , wnt signaling pathway , genetics
Excessive β‐catenin is considered to contribute to tumor progression by inducing transcription of cell cycle‐related genes such as cyclin D 1 and c‐myc . In contrast, our recent studies demonstrated that β‐catenin could inhibit cell proliferation through activation of p14 ARF /p53/p21 WAF1 pathway during trans ‐differentiation toward morular phenotype of endometrial carcinoma (Em Ca) cells. Here, we focused on associations with alterations in p16 INK4A and pRb expression during this process. In clinical cases, p16 INK4A immunoreactivity was found to frequently overlap with nuclear β‐catenin accumulation in small‐sized morules and surrounding glandular carcinomas (Sur‐Ca), demonstrating a significant positive correlation ( r = 0.447, p < 0.0001) overall, while the immunoreactions showed stepwise decrease in enlarged morules, despite persistent accumulation of β‐catenin and p21 WAF1 in nuclei. Immunoreactivity for both total pRb and its phosphorylated form was apparently decreased in all morules as compared to Sur‐Ca lesions, with a significantly positive correlation. In cell lines, transcriptional activation of p 16 INK 4A promoter by active form β‐catenin, as well as p21 WAF1 , occurred through the region from −385 to −280 bp relative to the translation start site, in a TCF4‐independent manner. Moreover, cell proliferation was accompanied with phosphorylation of pRb and increased p16 INK4A expression, while its inhibition by serum starvation caused decreased expression of total pRb but not p16 INK4A , resulting in high relative amounts of the latter. These findings indicate that induction of p16 INK4A mediated by nuclear β‐catenin and p21 WAF1 , along with loss of pRb expression, may be important for initial steps during trans ‐differentiation of Em Ca cells. In addition, its down‐regulation is associated with progression of lesions. © 2006 Wiley‐Liss, Inc.