No abstract

The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed.

In developing muscle cells environmental stimuli transmitted by purines binding to the specific receptors are crucial proliferation regulators. C2C12 myoblasts express numerous purinergic receptors representing both main classes: P2X and P2Y. Among P2Y receptors we have found the expression of P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 and P2Y 12 family members while among P2X receptors P2X 4 , P2X 5 and P2X 7 were discovered. We have been able to show that activation of those receptors is responsible for ERK class kinase activity, responsible for regulation of cell proliferation pathway. We have also demonstrated that this activity is calcium dependent suggesting Ca 2+ ions as secondary messenger between receptor and kinase regulatory system. More specifically, we do suspect that in C2C12 myoblasts calcium channels of P2X receptors, particularly P2X 5 play the main role in proliferation regulation. In further development of myoblasts into myotubes, when proliferation is gradually inhibited, the pattern of P2 receptors is changed. This phenomenon is followed by diminishing of the P2Y 2 -dependent Ca 2+ signaling, while the mRNA expression of P2Y 2 receptor reminds still on the high level. Moreover, P2X 2 receptor mRNA, absent in myoblasts appears in myotubes. These data show that differentiation of C2C12 cell line satellite myoblasts is accompanied by changes in P2 receptors expression pattern.Abbreviations: 2MeSADP -2-methylthio-ADP; BzATP -3 0 -0(4-benzoyl)benzoyl ATP; [Ca 2+ ]i -intracellular Ca 2+ concentration; DMEM -Dulbecco's modified essential medium; ERK -Ras/extracellular signal-regulated kinase; FCS -fetal calf serum; GAPDH -glycerol 3-phosphate dehydrogenase; HS -horse serum; InsP 3 -inositol 1,4,5-trisphosphate; PLCphospholipase C; PPADS -pirydoxal-phosphate-6-azophenyl-2 0 , 4 0 -disulphonic acid