Abstract NOTCH proteins have been implicated in multiple cellular functions, such as stem cell maintenance and cell fate determination. Initially identified as proto-oncogenes because they promote the development of certain types of leukemia, inactivating mutations of NOTCH were later reported. Together with the potential distinct functions of NOTCH family members, their ligands and associated niches, the precise roles of NOTCH in human cancers, particularly solid tumors, remain unsettled. In oral squamous cell carcinoma (OSCC), mutations of NOTCH1 are found in 10% to 15% tumors from Caucasian patients, mostly inactivating mutations. Recent studies of OSCC from Chinese patients, however, showed mutation rates of NOTCH1 about 50% with a considerable portion of potential activating mutations. These findings add another twist into the already complex picture of NOTCH alterations in human cancers, calling for further investigation to uncover what role exactly these molecules play in cancer initiation and progression to develop strategies targeting NOTCH signaling for cancer prevention and treatment. The NOTCH signaling pathway is evolutionally conserved and critical in stem cell differentiation and cell fate determination in development. Its roles in malignant initiation and progression, however, are complex and appear organ/cell-type dependent. Four NOTCH receptors (NOTCH 1-4) exist in mammals with a different number of EGF-like repeats and are activated upon binding to ligands (1). The activation requires two sequential protein cleavage steps by ADAM 10/17 metalloproteases and presenilin-y-secretase complex (y-secretase) to release the intra-cellular portion of the NOTCH, also known as ICN, which is translocated into the nucleus and mediates activation of the NOTCH pathway (2-4). Therefore, NOTCH pathway activities can be impacted by not only NOTCH receptors themselves but also their ligands, the protein cleavage steps, and ICN nuclear translocation.
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