Figure 1. Representative section of human skin. The various epidermal and dermal layers and the position of the melanocytes within the basal layer of the epidermis are indicated.

Figure 2. Example of a superficial spreading melanoma (a) and a nodular melanoma (b). (Kindly provided by Dr Paul Duray.)

Figure 3. Alternative transcripts and products encoded by the CDKN2A locus. Alternative splicing occurs, indicated by the dotted lines, to produce two transcripts: exons that splice to encode p16 (light shading) and those that encode p14^ARF (dark shading).

Figure 4. p16 inhibits entry into the cell cycle by inhibiting cyclin D/CDK4. p16 expression is induced during both replicative and premature senescence. For progression from G₁ into S phase, retinoblastoma protein (pRb) must be phosphorylated by the cyclin D/CDK4 complex which results in the release of the E2F transcription factors and transactivation of their target genes. p16 inhibits this pathway by inhibiting assembly of cyclin D and CDK4.

Figure 5. Antagonism of HDM2 by p14^ARF results in stabilization of p53. HDM2 functions to inhibit the activity and levels of p53 under normal conditions. p14^ARF expression is induced during senescence. p14^ARF binds to HDM2 and antagonizes its ability to regulate p53, thereby leading to p53 stabilization and G₁/S arrest or apoptosis depending on the cellular context.

Figure 6. PTEN inhibits the PI3-kinase/Akt signaling pathway. Signals from extracellular growth factors transduced through receptor tyrosine kinases lead to the recruitment of the phosphoinositide 3 kinase (PI3K) and phosphorylation of the phosphatidylinositol 3,4,5-triphosphate (PIP3) second messenger PI(4,5)P2 at the D-3 position. PI(3,4,5)P3 then recruits cytosolic signaling proteins to the membrane, for example Akt (also known as PKB). Subsequent activation of Akt then results in the phosphorylation of a range of downstream targets involved in cell proliferation and apoptosis. PTEN antagonizes this signaling pathway by dephosphorylating PI(3,4,5)P3.

Figure 7. Ras/Raf/MAPK pathway. BRAF functions downstream of Ras in the MAPK pathway. Signals from extracellular growth factors transduced through receptor tyrosine kinases result in activation of BRAF and the MAPK phosphorylation cascade. This results in activation of several nuclear transcription factors leading to cell proliferation.