Melanoma Molecular Maps Projects



Title: Cell senescence and escape mechanisms
Legend: Cell senescence is a physiological state in which cells loose their potential of proliferating [1]. Withdrawal of mitogens (growth factors) arrests normal cells in G0 (quiescence). All other stresses and factors arrest cell cycle beyond the restriction point in G1 and G2 (non-G0 arrest), in the presence of mitogenic stimulation. Strong mitogenic stimuli by themselves cause non-G0 arrest. Unlike G0, arrest beyond restriction point is characterized by both high levels of cyclins and CDK inhibitors, activated mitogenic pathways and continuous mass growth (cell hypertrophy). Prolonged hypertrophic arrest culminates in cell senescence. As shown in this Biomap, senescence can be induced by telomeric (replicative senescence, triggered by telomere exhaustion) and non telomeric signals (senescence prematurely induced by DNA damage as well as the overactivity of oncogenes such as mutant BRAF and NRAS, which are commonly found in human nevi and melanoma). In benign nevi, which consist of senescent melanocytes, oncogene-induced senescence represents a critical block of progression to melanoma [2]. Like with apoptosis, malignant cells develop mechanisms to escape senescence [3]. Besides the escape mechanisms described in different tumor types, in melanoma p14/ARF (inhibits E2F1 function in an animal melanoma model) [4] and c-Myc (inhibits senescence induced by overactive BRAF and NRAS in a human melanoma model) [5] appear to play a significant role (in opposite directions). Moreover, highly penetrant p16(INK4a) variants (R24P and A36P) fail to initiate melanoma cell senescence [8]. Senescence can act as a tumor suppressor mechanism, as demonstrated by somatic cell hybridization studies showing that a hybrid cell generated by fusion of a tumor (immortal) and a normal (mortal) cell always undergoes senescence in culture [6]. Thus, the senescent phenotype is dominant over immortality, which is a recessive trait. Accordingly, senescence inducing strategies are being developed as a novel anticancer approach [7]. CITED MOLECULES: BMI-1, (BMI1), CBX-7 (CBX7), CDK (cyclin dependent kinase), c-Myc, E2F1, ETS, HDM2 (MDM2), ID-1 (ID1), MEK, p14 (ARF), p16, p21, p53, PML, pRB (retinoblastoma protein), proteasome, Ras, Raf, Seladin-1. REFERENCES: [1] Blagosklonny MV, J Cell Physiol 2006, 209:592-7. [2] Courtois-Cox S, Oncogene 2008, 27:2801-9. [3] Prieur A, Curr Opin Cell Biol 2008, 20:150-5. [4] Ha L, Proc Natl Acad Sci USA 2007, 104:10968-73. [5] Zhuang D, Oncogene 2008, Epub ahead of print. [6] Smith JR, Science 1996, 273:63-67. [7] Schmitt CA, Biochim Biophys Acta 2007, 1775:5-20. [8] Haferkamp S, Aging Cell 2008, 7:733-45. Figure #71
Author: The MMMP Team (updated: August 2008)

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