NF-Y–Dependent Cyclin B2 Expression in Colorectal Adenocarcinoma

Abstract

Purpose: Cyclin B2, a G 2 -M cyclin, is overexpressed in colorectal adenocarcinomas compared with the normal mucosa. This study examined the level of cyclin B2 overexpression according to the histologic findings and investigated the mechanism(s) and clinical implications of cyclin B2 overexpression in colorectal adenocarcinomas. Experimental Design: The immunoreactivity of the polyclonal antibodies to cyclin B2 was determined in colorectal cancer cells. The transcriptional regulation of cyclin B2 by NF-Y was analyzed using an in vitro transfection assay and an in vivo chromatin immunoprecipitation assay. The proliferative activity of the colorectal cancer cells in relation to cyclin B2 overexpression was further examined. Results: The cytoplasmic distribution of cyclin B2 immunoreactivity was positive in 42 of 65 (64.6%) cases of colorectal adenocarcinoma, and the level was similar regardless of the histologic type. A dominant-negative form of NF-YA effectively inhibited the cyclin B2 promoter activity, and NF-Y was found to bind three conserved CCAAT boxes in the cyclin B2 promoter in colorectal adenocarcinoma cells.Tumor cells with a higher functional cyclin B2 activity grew faster than those with a lower activity. Furthermore, there was a correlation between the cells showing immunoreactivity to cyclin B2 and those containing the proliferating cell nuclear antigen, a G 1 -S cyclin, which is also downstream of NF-Y in colorectal adenocarcinoma cells. Conclusions: Cyclin B2 seems to be a molecular marker of a colorectal adenocarcinoma and that its up-regulation and coordinate expression of the other cell cycle^related genes by NF-Y might contribute to tumor cell proliferation by accelerating cell cycle progression.Mitosis is induced by the activation of the M-phasepromoting factor, which is a protein kinase whose principal subunits are p34 cdc2 and cyclin B. Cyclin B is a regulatory subunit that varies in abundance throughout the cell cycle (1). The metaphase to anaphase transition marks the end of mitosis and is induced by the degradation of cyclin B, which in turn leads to the inactivation of M-phase -promoting factor. As the cell cycle progresses, cyclin B begins to accumulate when the cell enters the interphase, which is followed by the reactivation of M-phase -promoting factor and another round of mitosis. Therefore, the B-type cyclins are the primary mitotic cyclins, although several yeast B-type cyclins have been reported to function earlier in the cell cycle, particularly in the S phase (2, 3). There are two mammalian B-type cyclins, cyclins B1 and B2, which differ in their NH 2 termini but have 57% similarity (4 -6). Cyclins B1 and B2 are coexpressed in most dividing cells and, in association with cdc2, play a role in entering the G 2 -M phase, although their subcellular localization differs (7). Cyclin B1 is primarily cytoplasmic but constantly shuttles between the nucleus and the cytoplasm during the interphase. At the end of the prophase, cyclin B1 rapidly translocates to the nucleus (8, 9)...

HMGA Proteins Up-regulate CCNB2 Gene in Mouse and Human Pituitary Adenomas

“…Consistent with this finding, ccnb2-knockout mice, although develop normally, are smaller than normal mice and have reduced litter sizes, which suggests that cyclin B2 expression gives some growth advantage (16). Moreover, several studies have reported the accumulation of Cyclins B1 and B2 in human malignant tumors, such as colorectal and lung cancer (17)(18)(19)(20). Also, in human pituitary adenomas cyclins amplification and overexpression have been observed (21)(22)(23).…”

“…Both B-type cyclins, in association with cdc2, play a critical role in regulating the G 2 -M phase transition of the cell cycle (15). Consistent with a general role in cell growth, several studies have reported the accumulation of cyclins B in human tumors, including pituitary adenomas (17)(18)(19)(20)(21)24). However, cyclin B2 involvement in pituitary tumorigenesis has not emerged yet, and the molecular mechanisms underlying its deregulation in cancer have not been definitively elucidated.…”

“…However, cyclin B2 involvement in pituitary tumorigenesis has not emerged yet, and the molecular mechanisms underlying its deregulation in cancer have not been definitively elucidated. Indeed, it is known that CCNB2 promoter is activated by NF-Y (25), but very little is known about its regulation in tumors (20).…”

Identification of Biomarkers for Diagnosis of Gastric Cancer by Bioinformatics

“…Although the present evidences of direct association between CCNB2 and GC progression are rare, CCNB2 may be another key regulator in GC development. At last, CCNB2 has been identified as a biomarker for the diagnosis of other cancers, such as lung cancer (Hofmann et al, 2004), colorectal cancer (Park et al, 2007) and cervical cancer (Garcia et al, 2013). These evidences suggest that CCNB2 may be a potential biomarker for diagnosis of GC.…”

Oncogenic Functions of Secreted Frizzled-Related Protein 2 in Human Renal Cancer

“…Cyclin B2 is one of essential components of the cell cycle regulatory machinery and has important roles in the control of the cell cycle at the G 2 -M-phase transition (32). The accumulation of cyclin B2 was also found in human malignant tumors (33)(34)(35). Cyclin E2 is a regulatory subunit of the CDK2 complex and accelerates the G 1 -S-phase transition (36).…”