Anticancer Mechanism of Cardiac Natriuretic Peptides via Targeting the Ras-MEK 1/2-ERK 1/2 Kinase Cascade

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Ras proteins play major roles in normal cell growth, malignant transformation and learning and memory (Denayer et al., 2008). The genes encoding Ras proteins were first identified as homologues of rodent sarcoma virus genes. In 1982 human DNA sequences homologous to the transforming oncogenes of the v-Harvey (HRAS) and Kirsten (KRAS) rat sarcoma virus were identified in DNA sequences derived from a human bladder and a human lung cancer cell line, respectively (Der et al., 1982). Since then findings have pointed to the important role of Ras genes as oncogenes and it soon became clear that encoded proteins were constitutively active due to point mutations in the Ras genes (Denayer et al., 2008). Any form of somatic, and most recently germline mutations in Ras genes, in several of their upstream and downstream molecules have been reported to result in different human malignancies (Denayer et al., 2008). Some of these mutations in genes and the various protein components they encode have been recognized in a group of phenotypically overlapping disorders, referred to as the neuro-cardio-facial-cutaneous syndromes (Denayer et al., 2008). Patients with such disorders experience variable degrees of psychomotor delay, cardiac abnormalities, facial dysmorphism, short stature, skin defects and increased cancer risk (reviewed in Denayer et al., 2008). This therefore points to the significant roles for a evolutionary conserved pathway not only in oncogenesis, but also in cognition, growth and development (reviewed in Denayer et al., 2008). Other known constitutional disorders caused by mutated Ras pathway genes point to involvement of the Ras-MAPK pathway in immune modulation and vascular development(reviwed in Denayer et al., 2008). ... ... middle of paper ... ...9. Four cardiac hormones inhibit insulin’s mitogenic action via inhibiting Ras. CancerTherapy Vol 7, 367-372. 17. Takai Y, Sasaki T, Matozaki T.2001. Small GTP-binding proteins. Physiol Rev 81:153–208. 18. Tuveson DA, Shaw AT, Willis NA, Silver DP, Jackson EL, Chang S, Mercer KL, Grochow R, Hock H, Crowley D, Hingorani SR, Zaks T, King C, Jacobetz MA, Wang L, Bronson RT, Orkin SH, DePinho RA, Jacks T.2004. Endogenous oncogenic K-ras (G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5:375–387. 19. Vesely DL. 2010.Metabolic targets of cardiac hormones' therapeutic anti-cancer effects. Curr Pharm Des.16 (9):1159-66. 20. Wajapeyee N., R.W. Serra, X. Zhu, M. Mahalingam and M.R. Green. 2008. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132 pp. 363–374.

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