A protein strongly contributing to the stability of p53 is poly(A

A protein strongly contributing to the stability of p53 is poly(ADP-ribosyl) polymerase-1 (PARP-1) [38, 42, 43], a protein that enzymatically modifies p53 [19, 41] thereby preventing its nuclear export [19, 39] by impeding the binding to CRM1 [19]. A protein that retains p53 in the cytoplasm preventing its nuclear functions, is mortalin, a member of the heat shock protein 70 (HSP70) family.

Mortalin binds p53 [31] and inhibits its pro-apoptotic functions what leads www.selleckchem.com/products/azd9291.html to increased tumor MLN2238 nmr development [31, 37]. The constitutive overexression of p53 in cells or animals is not feasible because this would trigger apoptosis or at least cell cycle arrest, making a functional study of the proteins’ features impossible. Fortunately, a temperature-sensitive (ts) mutant of p53 that displays wt properties at 32˚C but mutant character at elevated temperature [25], can be used to perform experiments aimed to elucidate its functions. This ts mutant demonstrates selleck screening library clear properties of mutant p53 at 39°C. At 37°C the cells also behave like mutant cells although a small portion of

p53 protein is in wt conformation. However, mutated p53 protein localized in the cytoplasm impedes the action of the wt protein. Thereby, the conformation and activity of p53 can be changed at will by simply growing the cells at 37 or 39˚C. The decision of p53 to trigger cell cycle arrest or apoptosis depends on the severity of the damage and is also regulated on the transactivational level by the use of p53 responsive elements to which the protein has different binding affinity [16]. In general, p53 binds to targets P-type ATPase mediating cell cycle arrest with a higher affinity

than to those which induce apoptosis [16]. A recent publication also showed that p53 is capable of inducing anti-apoptotic targets [17], adding further complexity to the functions and activities of the tumor suppressor protein. Also the Ras proteins are important for tumor development. In their active form they reside in the cytoplasmatic membrane and transmit signals from growth factor stimulation and downstream targets involve Raf-1 and PI3-kinase. Gain of function mutations lead to a constitutively active Ras protein that sustains growth-promoting signals, irrespective of extracellular stimulation, resulting in uncontrolled proliferation. For its proper anchoring in the cytoplasmic membrane and activity, Ras has to be isoprenylated by farnesyl protein transferases (FPTases) or/and geranylgeranyl protein transferases. Therefore, inhibitors of farnesylation have been used for treatment of cancers with constitutively activated RAS. Interestingly, tumor cells with constitutively activated RAS are rendered prone to treatment with pharmacological inhibitors of cyclin-dependent kinases (CDKs) like roscovitine (ROSC) and olomoucine (OLO) when they are pre-treated with FTIs [45].

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