MCC, a Cytoplasmic Protein That Blocks Cell Cycle Progression from the G0/G1 to S Phase

Abstract

The MCC gene was isolated from the human chromosome 5q21 by positional cloning and was found to be mutated in several colorectal tumors. In this study, we prepared specific antibodies and detected the MCC gene product as a cytoplasmic 100-kDa phosphoprotein in mouse NIH3T3 cells. Immunoelectron microscopic analysis showed that the MCC protein is associated with the plasma membrane and membrane organelles in mouse intestinal epithelial cells and neuronal cells. The amount of the MCC protein remained constant during the cell cycle progression of NIH3T3 cells, while its phosphorylation state changed markedly in a cell cycle-dependent manner, being weakly phosphorylated in the G0/G1 and highly phosphorylated during the G1 to S transition. Overexpression of the MCC protein blocked the serum-induced cell cycle transition from the G1 to S phase, whereas a mutant MCC, initially identified in a colorectal tumor, did not exhibit this activity. These results suggest that the MCC protein may play a role in the signaling pathway negatively regulating cell cycle progression.

Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer

“…Overexpression of wild-type MCC protein in vitro resulted in a decrease in the number of cells entering the cell cycle S phase. This cell cycle inhibitory effect was completely abolished using mutant forms of the MCC protein (Matsumine et al, 1996). One mutation tested was the same as that initially identified in a tumor from a colorectal cancer patient (Kinzler et al, 1991).…”

“…The MCC protein becomes highly phosphorylated during the G1-to S-phase transition in vitro and is a potential negative regulator of cell cycle progression (Matsumine et al, 1996). Overexpression of wild-type MCC protein in vitro resulted in a decrease in the number of cells entering the cell cycle S phase.…”

“…Early reports indicated that loss of heterozygosity (LOH) at the MCC locus is common, that is, B42% in colorectal cancers (Ashton-Rickardt et al, 1991), whereas somatic mutation of MCC is relatively rare, 3-7% (Nishisho et al, 1991). More recent studies have shown that the wild-type MCC protein may have a functional role in important cellular processes relevant in carcinogenesis, such as cell cycle regulation and the nuclear factor-kB (NF-kB) pathway (Matsumine et al, 1996;Bouwmeester et al, 2004). The activation and translocation of NF-kB to the nucleus is part of a signal-transduction pathway, which forms a basis for several physiologic and pathologic processes including cancer.…”

Mutated in colorectal cancer, a putative tumor suppressor for serrated colorectal cancer, selectively represses β-catenin-dependent transcription

“…Also both MCC and MCC2, the only MCC homologous gene isolated, contain a C-terminal PSD-95/Discs-large/ZO-1 (PDZ) domain-binding ligand sequence (Senda et al, 1999;Ishikawa et al, 2001;Nourry et al, 2003). MCC was also found to negatively regulate cell cycle in NIH3T3 cells (Matsumine et al, 1996), suggesting a role of MCC in cell growth regulation. Moreover, MCC is highly expressed in murine colonic surface epithelial cells and other types of well-differentiated cells (Matsumine et al, 1996;Senda et al, 1999) indicating a potential general physiologic role for MCC in cell differentiation.…”

“…The three previous studies hinted that MCC may be important in several cellular processes involved in the development of cancer (Matsumine et al, 1996;Senda et al, 1999;Bouwmeester et al, 2004). MCC was previously found to be localized to the cytoplasm and membrane-cytoskeletal components (Senda et al, 1999).…”