The Role of Intrinsic Signaling Pathways in Cell Proliferation

Abstract

Programmed cell death, or apoptosis, and controlled cell division, or mitosis, are two highly regulated processes in the cell cycle. A balance between apoptosis and mitosis is critical for multiple distinct states including embryonic development, immune cell activation, stem cell differentiation, tissue formation (wound healing), and tumor prevention, among others. A cell undergoing apoptosis shows a series of characteristic morphological changes similar to normal mitosis and an aberrant form of mitosis. During each of these processes, nuclear chromatin condenses, the nuclear lamina and cytoplasmic membranes disintegrate, and cells decrease in volume. The morphological resemblance among cells undergoing these processes suggests that the underlying intracellular signaling pathways influence the mitotic cell fate. In this paper, the relationship of intracellular signaling pathways, cell cycle dynamics, and apoptotic cell signaling pathways is discussed. The mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/Ras/Raf/ERK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), Janus kinase/signal transducer and activator of transcription (JAK/STAT), wingless-related integration site (Wnt), and transforming growth factor beta (TGF-[Formula: see text] are major cell signaling pathways that transmit signals from multiple cell surface receptors to transcription factors in the nucleus. The pathways are stimulated by cytokines, growth factors, and external stimuli, i.e., reactive oxygen species which induce signal transduction pathways and regulate complex processes such as cell cycle progression, cell proliferation, cellular growth, differentiation, and apoptosis. Aberrant mutations in particular genes and proteins of these pathways contribute to cancers usually by inhibiting pro-apoptotic proteins (e.g., Bak, Bax, Noxa, Puma, etc.) and stimulating antiapoptotic proteins (e.g., Bcl-2, Bcl-XL, Mcl-1, etc.). The cell cycle is regulated by intracellular signaling pathways such as the MAPK/Ras/Raf/ERK and PI3K pathways to produce the synthesis of cyclin D and other mitosis regulating proteins (Myc and Jun). Cyclin D1 binds to cyclin-dependent kinase (CDK) 4 and CDK 6 (CDK4/6) to form an effective complex, activate several substrates, and initiate the cell cycle. The prominent molecules that regulate signaling pathways in normal and cancer cells are described.