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Figure 3.3.1.E. Negative regulation of RAS signaling. The liga-tion of growth factor receptors often activates the RAS pathway and leads to cell cycle progression through MEK and ERK. This cascade is subject to negative regulation, or inhibition at multiple levels. The negative regulators PP2A, RAP-1, and ARHI have tumor-suppressing properties.

carcinoma are typically acquired activating mutations of K-ras. A point mutation in the second exon of the H-ras-1 gene may occur in melanoma.

• The highly polymorphic H-ras-1 mini-satellite locus downstream of the proto-oncogene consists of four common progenitor alleles and a multitude of rare alleles, which may derive from mutations of the progenitors. Polymorphisms in this locus have significant associations with carcinomata of the breast, colorectum, and urinary bladder, and with acute leukemia [Krontiris et al. 1993].

• Costello syndrome (Faciocutaneoskeletal syndrome, FCS syndrome) comprises short stature, redundant skin of the neck, palms, soles, and fingers, curly hair, papillomata around the mouth and nares, and mental retardation. The levels of the catecholamine metabolites vanillylmandelic acid and homovanillic acid in the urine of patients with Costello syndrome are elevated. The condition is caused by the germline mutation G12V of H-RAS. Some patients develop rhabdomyosarcoma [Kerr et al. 1998] or bladder carcinoma [Franceschini et al. 1999], suggesting an increased tumor risk associated with the disease.

• Normal cells respond to inappropriate growth signals by inducing tumor suppressor genes. In these cells, the expression of oncogenic RAS induces the expression of p16INK4a and p53. Therefore, immortalization, which in epithelial cells is frequently associated with the loss of P16, is a prerequisite for transformation by RAS.

• In the presence of active RAS, TGF-P turns from a tumor suppressor, capable of inducing growth arrest and apoptosis into an inducer of tumor progression. This is due to the induction of MAPK and PI 3-K by RAS. The MAPK pathway cooperates with TGF-P to drive metastasis, while signaling through Phosphatidylinositol 3-Kinase protects from the lethal effects of TGF-P.

• RAS-GAPs are negative regulators of RAS signaling, because they stimulate the hydrolysis of GTP by RAS. However, in cancer cells that express an oncogenic form of RAS, RAS-GAP can no longer inactivate RAS signaling. Instead, it acts as a RAS effector, promoting cell proliferation. An interaction between the SH3 (SRC homology 3) domain of RAS-GAP and the kinase domain of the serine/threonine kinase Aurora may account for this effect. The interaction may directly or indirectly regulate Aurora activity, which is required for mitosis. The antiapoptotic protein Survivin can form a complex with Aurora and RAS-GAP, with the ternary complex regulating cell division and apoptosis in tumor cells [Gigoux et al. 2002].

• B-raf is frequently mutated in cancer and becomes oncogenic. Mutations occur in the exons 11 and 15. They include V600, L597, D594, G468, G466, and G464 and increase the kinase activity of B-RAF. B-raf is mutated in about two thirds of all melanomata [Davies et al. 2002], in sporadic col-orectal tumors with microsatellite instability, in low-grade ovarian serous carcinoma, and in thyroid papillary cancer. 80% of tumor-associated mutations in B-raf correspond to the hot spot transversion mutation T1799A that causes the amino acidic substitution V600E. The other 20% accounts for a wide variable range of missense mutations, all of which reside in the glycines of the G-loop in the exon 11 or in the activation segment in exon 15 near the V600. The mutation V600E confers transformant activity to the cells because it mimics the phosphorylations of T599 and S602.

• c-raf-1 may be involved in mixed parotid gland tumors with the t(3;8)(p25;q21) translocation.

• Neurofibromatosis 1 (NF1) is a autosomal dominant familial cancer syndrome, in which patients develop multiple benign and malignant tumors of the central and peripheral nervous system. Consistent features of this disorder are café au lait spots and fibromatous skin tumors. Type I von Recklinghausen [von Recklinghausen 1882] or classical peripheral neurofibromatosis (NF1) is relatively common with a prevalence of 1 in 3,000 live births in Western countries. A nf1 microdeletion is the most frequent mutation in individuals with neuro-fibromatosis 1. The loss of both nf1 alleles is causative for the fibromata, myeloid leukemias (especially, juvenile myelomonocytic myeloid leukemia, JMML), and pheochromocytomata associated with the syndrome. It also leads to the development of numerous neurofibromata in the Schwann cells of peripheral nerves, which become malignant peripheral nerve sheath tumor (MPNST) in 3-15% of cases. Although the benign tumors of neurofibromatosis are multiclonal, the malignant lesions, neurofibrosarcomata, are monoclonal. Gastrointestinal complications of neurofi-bromatosis 1 arise during midlife, later than the cutaneous lesions, with a frequency of 12-60% of cases. Pheochromocytoma is not the only cause of hypertension in patients with neurofibromatosis 1, renal artery stenosis due to vascular neuro-fibromatosis is a relatively common cause.

• Expression of the oncogenic COOH-terminally truncated COT results in substantially increased SAPK and ERK activation, because the negatively regulating activity of the COOH-terminal domain is lacking. Consecutive to a 3' end mutation, cot (map3k8) becomes a transforming gene in lung ade-nocarcinoma. The mutation is localized to exon 8.

• The oncogenic potential of COT is associated with thymomata. In correspondence with the broad effector specificity of COT, COT-dependent transformation requires P38, SAPK, and ERK5.

• In melanoma cells, the signaling cascade ASK1^MKK6^P38HOG silences the cd95 (fas) promoter via a NF-kB/SP-1 site. This occurs through inhibition of I-KBa phosphorylation, thereby limiting NF-kB activity. The lack of CD95 expression renders the melanoma cells resistant to apoptosis [Ivanov and Ronai 2000].

• AP-1 is constitutively activated with robust JUN and JUN-B overexpression in Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL), but not in other lymphoma types. While AP-1 supports proliferation of Hodgkin cells, it suppresses apoptosis in ALCL cells. Furthermore, the BCR-ABL fusion protein activates the JNK signaling pathway in hematopoietic cells and increases transcriptional activity mediated by the transcription factor AP-1. JNK-1 is required for the survival of the transformed cells in the absence of stromal support. Failure to survive is associated with decreased expression of BCL-2.

• Transformed cells express elevated levels of eIF4E. This leads to disordered growth and enhances the translation of cyclin D1 mRNA. Oncogenic RAS induces increased phosphorylation of eIF4E, and the ability of RAS to transform cells is diminished when eIF4E expression is decreased, implying that eIF4E is a key mediator of RAS-induced transformation [Flynn and Proud 1996].

• ARHI is consistently expressed in normal breast epithelial cells but is dramatically down-regulated in more then 70% of breast and ovarian cancers.

3.3.2 Protein Kinase C pathways

Cascades of protein phosphorylation on serine or threonine residues can transduce signals to the nucleus. They may be activated after ligation of protein tyrosine kinase receptors via PLC-y, or after engagement of G-Protein-coupled receptors via PLC-P. An important pathway in cell cycle progres sion is constituted by the hydrolysis of phos-phatidylinositol 4,5-bisphosphate by Phospholipase C to diacylglycerol and inositol 1,4,5-trisphosphate. While inositol 1,4,5-trisphosphate stimulates calcium mobilization, diacylglycerol activates PKC.

Protein Kinases C constitute a family of 12 distinct serine/threonine kinases that participate in signaling involved in cellular proliferation and differentiation. All forms are composed of a NH2-terminal regulatory domain and a COOH-terminal catalytic domain (Figure 3.3.2.A). Two characteristic cysteine-rich repeats are conserved among nearly all members of the PKC family. The classical PKCs a, P1, P2, and y are calcium dependent. The PKCs 8, e, n, and 0, do not depend on calcium. The atypical PKCs Z (PKC2) and i/^ do not bind either calcium or phorbol esters. The PKC P gene codes for two distinct proteins generated by alternative splicing. A distinct subclass of PKCs with unique characteristics is constituted by PKC |i (PKD) and v, which, unlike other PKCs, contain a Pleckstrin homology domain. PKC | is a downstream target of the P and y subunits of heterotrimeric G-Proteins. GPy binds to the Plekstrin homology domain, resulting in the activation of PKC This interaction regulates the dynamics of Golgi membranes and protein secretion.

Adapter proteins are key to organizing signaling enzymes near their select substrates and away from others in order to optimize the precision and speed of the response. RACKs (Receptors for Activated C-Kinase) are isoenzyme-selective adapter proteins for individual PKC isoenzymes. In addition to anchoring activated PKC isoenzymes, RACKs anchor other signaling enzymes.

- RACK1, the anchoring protein for activated PKCPII, binds the tyrosine kinase SRC, certain Integrins, and Phosphodiesterase.

- RACK2, the PKCe-specific RACK, is a coated vesicle protein and thus is involved in vesicular release as well as cell-cell communication.

At least some of the proteins that bind to RACKs, including PKC itself, regulate cell growth [Schechtman and Mochly-Rosen 2001].

PKC signaling induces the expression of various genes that drive cell cycle progression.

- PKC may activate the MAP Kinase pathway, resulting in cell proliferation.

- Members of the PKC family of enzymes are capable of translocating to the nucleus or are resident within the nucleus. PKC can alter transcription through the phosphorylation of AP-1 (Activator Protein-1).

PKC family of proteins (human)

□ C-1 □ C-1 fJCa-binding ^ C-1 [_] C-1 Qca-binding][

S/T Kinase



S/T Kinase tr

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