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In most cell types, this would be Cyclin D1, Cyclin D2 and D3 being involved in a more restricted range of cell types.

consequentially. The Cyclin E gene promoter is activated by E2F1. So, as RB1 starts to become hyperphosphorylated and less capable of inhibiting E2F, more Cyclin E is produced leading to still higher activity of CDK2. This autocatalytic loop eventually leads to irreversible commitment to S-phase, but is limited by p27KIP1.

For CDK2 to become fully active, the p27KIP1 inhibitor must be removed. This occurs by successive phosphorylation, oligo-ubiquitination, and proteolytic degradation. In normal cells, the down-regulation of p27KIP1 is a gradual process which accelerates when CDK2 becomes sufficiently active to phosphorylate some of the inhibitor protein, thereby liberating further CDK2 molecules to phosphorylate more p27KIP1, in another autocatalytic loop. A crucial component in this process is MYC. MYC is induced by many growth factors, but its half-life and activity are also regulated by phosphorylation. ERK phosphorylation at Ser62 leads to increased stability and activity, whereas GSK phosphorylation at Thr58 has the opposite effect. So, again, the inhibitory phosphorylation of GSK by AKT synergizes with activation of the MAPK to activate MYC. Activation of MYC contributes to the increased transcription of Cyclin D1, CDK4, and CDC25A, and leads to a small decrease in transcription of p27KIP1. Moreover, MYC induces CUL1, a component of the protein complex that ubiquitinates p27KIP1. Still another mechanism involved is decreased translation of p27KIP1, likely as a consequence of PI3K activation. So, regulation of MYC and p27KIP1 are further points of synergy between the pathways.

The synergisms exerted on the regulation of the cell cycle by the concomitant activation of the MAPK and AKT pathways during normal cell proliferation are reflected in the alterations observed in cancers (Figure 6.7). Overactive receptor tyrosine kinases may be such potent oncogenes, since they are capable of activating both pathways. Oncogenic RAS may likewise activate both pathways, albeit less efficiently. Conversely, oncogenic MYC itself, while very efficient in promoting cell growth (also in a broader sense) and stimulating cell cycle progression, also tends to drive cells into apoptosis, which is again counteracted by factors that activate the PI3K pathway, such as IGF peptides or RAS mutations. This explains the cooperation of RAS-like and MYC-like oncogenes in rodent cell transformation assays (^4.3). This cooperativity is also at work in many human cancers.

However, these combinations of alterations are probably not sufficient to cause human cancers, since they are counteracted by further fail-safe mechanisms. The most important one may be activation of TP53 by hyperproliferation signals and through accumulation of CDK inhibitors like p16INK4A and p21CIP1 during continuous rapid growth of human cells. These fail-safe mechanisms lead to apoptosis in some cases, but more typically to replicative senescence (^7). Thus, at some point in the development of human cancers, latest during progression, these mechanisms need to be inactivated. The most radical way for their inactivation is loss of both RB1 and TP53. Another frequent mechanism is deletion of the CDKN2A locus encoding p16INK4A and p14ARF. Of note, while the prime significance of these alterations may be the inactivation of fail-safe mechanisms against hyperproliferation, they also decrease the dependence of tumor cells on external growth factors and increase their tolerance of genomic instability.

So, alterations that lead to an increased or constitutive activity of the MAPK and PI3K pathways may in some cases be self-limiting. At the least, they exert a strong selection pressure favoring further changes that lead to progression towards a more aggressive phenotype. This sort of progression is observed in many human cancers, in carcinomas (e.g. 13, 14, 19) as well as hematological cancers (^10).

Figure 6.7 An overview of alterations in MAPK and PI3K pathways in human cancers Alterations in the MAPK (right) and PI3K (left) pathways synergize to increase cell proliferation and growth and to decrease apoptosis. Prohibition sign: inactivation by deletion, mutation and/or promotor hypermethylation. Exploding star: Activation by mutation. Arrow down: decrease; arrow up: increase. Activities of both pathways are also induced by receptor tyrosine kinase overactivity or can partly be mimiced by oncogenic activation of transcription factors, especially of the MYC family (not shown).

Figure 6.7 An overview of alterations in MAPK and PI3K pathways in human cancers Alterations in the MAPK (right) and PI3K (left) pathways synergize to increase cell proliferation and growth and to decrease apoptosis. Prohibition sign: inactivation by deletion, mutation and/or promotor hypermethylation. Exploding star: Activation by mutation. Arrow down: decrease; arrow up: increase. Activities of both pathways are also induced by receptor tyrosine kinase overactivity or can partly be mimiced by oncogenic activation of transcription factors, especially of the MYC family (not shown).

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