The G proteins are guanyl nucleotide-binding proteins. The heterotrimeric, or large G proteins, link receptor activation with effector proteins such as adenylcyclase, which activates the cAMPdependent, kinase-signaling cascade (49). The monomeric or small G proteins, encoded by the ras proto-oncogene family, are designated p21 and are particularly important regulators of mitogenic signals. The p21 Ras protein exhibits guanyl triphosphate (GTP) binding and GTPase activity. Hydrolysis of GTP to guanyl diphosphate (GDP) terminates p21 Ras activity. The p21 Ras protein inﬂuences the production of deoxyguanosine (dG) and inositol phosphate (IP) 3, arachidonic acid production, and IP turnover.
Figure 6.5 The regulation of ovarian function occurs through autocrine, paracrine, and endocrine mechanisms.
The phosphoinositide 3 (PI3) kinase can be activated by various growth factors like platelet-derived growth factor (PDGF) or IGF results. Activation of PI3 kinase results in an increase of intracellular, membrane-bound lipids, phosphatidylinositol-(3,4)-diphosphate (PIP2), and phosphatidylinositol-(3,4,5)-triphosphate (PIP3). The Akt protein is subsequently phosphorylated by PIP3-dependent kinases (PDK) for full activation. Activated Akt is released from the membrane and elicits downstream effects that lead to an increase in cell proliferation, prevention of apoptosis, invasiveness, drug resistance, and neoangiogenesis (50). The Pten (phosphatase and chicken tensin homologue deleted on chromosome 10) protein is an important factor in the PI3 kinase pathway, because it counteracts the activation of Akt by dephosphorylating PIP3. Cells with mutated tumor suppressor gene Pten and lack of functional Pten expression display an increased proliferation rate and decreased apoptosis, possibly supporting the development of a malignant phenotype. Pten frequently is mutated in endometrioid adenocarcinoma. Furthermore, lack of functional Pten expression was described in endometriosis.
The mammalian target of rapamycin (mTOR) is regulated by the PI3 kinase pathway. mTOR is a serine/threonine protein kinase that regulates a variety of cellular processes, including proliferation, motility, and translation (51). mTOR integrates the input from various upstream pathways, including insulin and growth factors like IGF proteins. The mTOR pathway provides important survival signals for cancer cells and therefore was one focus of targeted drug development (52).
Figure 6.6 Pathways of intracellular signal transduction.
For example, rapamycin inhibits mTOR by associating with its intracellular receptor FKBP12. Derivates of rapamycin like everolimus (RAD001) and temsirolimus (CCI779) showed promising results in clinical trials (53).
mTOR functions as the catalytic subunit of two different protein complexes. Among the proteins associated with mTOR complex 1 (mTORC1) is mTOR, the regulatory associated protein of mTOR (Raptor), and PRAS40. This complex functions as a nutrient and energy sensor and controls protein synthesis (54). While mTORC1 is activated by insulin, growth factors, amino acids and oxidative stress, low nutrient levels, reductive stress, and growth factor deprivation inhibit its activity.
Figure 6.7 Proto-oncogenes are divided into subgroups based on their cellular location or enzymatic function.