# Peptides That Block RAS-p21 Protein-Induced Cell Transformation
### Mitogenic Signal Transduction Pathways Induced by RAS-p21
This all-important protein shuttles between the cytosol, where it is involved in cytoskeletal rearrangements (the name MAPK stands for mitogen activated or microtubule-activating protein kinase) and the nucleus in which it activates the critically important nuclear transcription factor, _fos_, that itself forms a heterodimer complex, called AP1, with the critically important nuclear transcription factor, _jun_, that is activated by another kinase, jun-N-terminal kinase (JNK), that is normally activated on a separate pathway called the stress-activated protein (SAP) pathway. The AP1 complex induces the transcription of many pro-mitogenic proteins including cyclins and nuclear skeletal proteins called nuclear matrix proteins ( or NMP's); other nuclear proteins, such as _myc_, also transcriptionally active, are also often activated in this process. Anti-oncogene proteins, such as p53, also become activated. This protein blocks the transcription of pro-mitotic proteins (minus sign on p53 arrow) and induces apoptosis in transformed cells. On the right of the figure, oncogenic RAS-p21 (RAS-p21*) is shown interacting with and activating JNK, which seems to be a unique aspect to oncogenic RAS-p21. Work in oocytes (see text) suggests that wild-type RAS-p21 may also activate the dual specificity kinase TOPK (not shown in the figure), which is known to bind to RAF and is in the MEK superfamily. Apparently, oncogenic RAS-p21 does not utilize this pathway. The activated state of RAS-p21 is regulated by the protein, GAP (GTPase-Activating Protein), that enhances the native GTPase activity of RAS-p21. GAP induces the hydrolysis of GTP to GDP, resulting in the inactivation of RAS-p21. However, GAP itself may be involved in mitogenic signal transduction, hence, the question mark in the arrow below the GAP box in the figure. As shown on the left side of the figure, RAS-p21 also interacts directly with phosphoinositol-3-hydroxy kinase (PI3K), which catalyzes the synthesis of phosphatidylinositol 3-hydroxyphosphate or triphosphate (PIP3) that is involved in the activation of protein kinase B (PKB), also known as AkT, of which among many functions, induces cell proliferation. Activated RAS-p21 further induces the activation of phospholipase C (PLC) that catalyzes the formation of diacylglycerolDAG), an activator of protein kinase C (PKC) that is especially critical to the oncogenic _RAS-p21_ pathway and the synthesis of inositol triphosphate (IP3) of which mobilizes the release of calcium. Once activated, RAS-p21 initiates a series of signal transduction pathways from the cell membrane to the nucleus, resulting in mitosis. In a critical signal transduction pathway [1], RAS-p21 binds to the critical serine/threonine kinase protein, RAF, which, upon binding to RAS-p21, activates a second critical serine/threonine kinase called MEK that, in turn, activates the all-important kinase, ERK (1 and 2), also called MAPK (extracellular mitogenic-activating protein kinase or microtubular-activating protein kinase), which upon activation, crosses the nuclear membrane and activates the vital pro-mitogenic transcription factor, fos. Activated fos forms a heterodimeric complex with the transcription factor, jun, which is activated by another kinase called jun kinase (JNK) that can be directly activated by oncogenic RAS-p21 (see below). As discussed further, the RAS-p21-RAF interaction is a site that can be targeted by a number of peptides that block this interaction. The fos-jun complex activates the transcription of pro-mitotic proteins including the cyclins and nuclear matrix proteins (NMPs in Figure 1) required for nuclear skeleton maintenance during mitosis. As also shown in Figure 1, there are a number of other pathways activated by RAS-p21. Activated RAS-p21 binds to and activates phosphoinositol-3-hydroxykinase (PI3K) [1], causing a direct increase in intracellular phosphatidylinositol triphosphate (PIP3) that is involved in the activation of protein kinase B (Akt), of which promotes mitogenesis (not shown in the figure).