The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Notch signaling plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. The notch cascade consists of notch and notch ligands, as well as intracellular proteins transmitting the notch signal to the cell's nucleus. In mammalian cells, there are four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4, which display both redundant and unique functions. Notch receptors are large single pass Type I transmembrane proteins. The extracellular domain of all Notch proteins contains 29–36 tandem epidermal growth factor (EGF)-like repeats, some of which mediate interactions with ligand. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Notch signaling is dysregulated in many cancers, and faulty notch signaling is implicated in many diseases including CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy), T-ALL (T-cell acute lymphoblastic leukemia), Alagille syndrome, MS (Multiple Sclerosis), and myriad other disease states.
Tumor suppressor are proteins that slow down cell division, inhibit apoptosis or programmed cell death. When tumor suppressors don't work properly, cells can grow out of control, which can lead to cancer. Many different tumor suppressor proteins have been found, including p53, BRCA1, BRCA2, APC, and Rb protein. A tumor suppressor is like the brake pedal on a car. It normally keeps the cell from dividing too quickly, just as a brake keeps a car from going too fast. When something goes wrong with the gene, such as a mutation, cell division can get out of control. An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated. Unlike the oncogene, tumor suppressor genes follow the "Two-hit hypothesis", which implies that both alleles that code for a particular protein must be affected before an effect is manifested. That means the mutation in tumor suppressor genes are recessive whereas mutant oncogenes are dominant.
TP53 gene encoding tumor suppressor protein p53 is normally found at low levels, but when DNA damage is sensed, p53 levels rise and initiate protective measures. p53 binds to many regulatory sites in the genome and begins production of proteins that halt cell division until the damage is repaired. Or, if the damage is too severe, p53 initiates the process of programmed cell death, or apoptosis, which directs the cell to commit suicide, permanently removing the damage.
pRB, the product of the retinoblastoma tumor suppressor gene, operates in the midst of the cell cycle clock apparatus. Its main role is to act as a signal transducer connecting the cell cycle clock with the transcriptional machinery. In this role, pRB allows the clock to control the expression of banks of genes that mediate advance of the cell through a critical phase of its growth cycle. Loss of pRB function deprives the clock and thus the cell of an important mechanism for braking cell proliferation through modulation of gene expression.