Tumor suppressor proteins

MDM2 Protein antagonist of p53 tumor suppressor protein Sarcomas... 

T., Hellman, U., Schwaetz, A. L., and Ciechanovee, A. The Tumor Suppressor Protein pl6 and the Human Papillomavirus oncoprotein E7-58 are Naturally Occurring Lysine-Less Proteins that are Degraded by the Ubiquitin System Direct Evidence for Ubiquitination at the N-Terminal Residue. J. Biol. Chem., 2004, 279, 41414-41421. 

Duan, D. R. et al. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science 1995, 269, 1402-6. 

Loneegan, K. M. et al. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. 

Ivan, M. and Kaelin, W. G., Jr. The von Hippel-Lindau tumor suppressor protein. Curr Opin Genet Dev 2001, 3 3, 27-34. 

Ubiquitination of a novel deubiq-uitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein, J Biol Chem,... 

Doyon Y, Cayrou C, Ullah M, Landry AJ, Cote V, Selleck W, Lane WS, Tan S, Yang XJ, Cote J (2006) ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell 21 51-64... 

DNA methylation may directly decrease the binding affinity of certain transcription factors to DNA [38]. Additionally, methylated CpG sites recruit MBD proteins, which in turn leads to transcriptional repression [39]. siRNA-mediated knockdown of MBD proteins leads to a re-expression of silenced tumor suppressor protein candidates [40]. DNA methylation and histone modification are dependent on each other [41, 42] and from this interplay a synergy in derepression (e.g. between histone deacetylase and DNMT inhibitors) can be observed [43—45] (see also below). 

The histone deacetylases are found in large protein complexes, often together with repressive transcription factors. By this token, interactions of the repressive heterodi-meric transcription factor Mad-Max and a complex with the histone deacetylase HDAC I and the mSinSA protein have been demonstrated. A complex of HDAC I and the nuclear receptor-corepressor (see chapter 4) binds to unliganded nuclear receptors and is believed to exercise a repressive effect. A further example is the tumor suppressor protein pRb (see chapters 13,14), which can occur as a transcription repressor in the hypo-phosphorylated form and transcriptionally activating in the hyperphosphorylated form. The repressive form of the pRb protein recruits the histone deacetylase HDAC 1 to the DNA and thereby initiates an active repression of the gene (see 13.3.2). 

The discovery of this family of E3 enzymes started from the studies on the targeted degradation of the p53 tumor suppressor protein. Ubiquitinylation and degradation of p53 can be mediated by the papillomavirus E6 oncoprotein (see below) in collaboration with a further protein, E6-AP (E6 associated protein). E6-AP was the first member of a large family of E3 enzymes, the Hect (homologous to E6-AP C-terminus ) domain family. These proteins contain an essential active site Cys residue near the C-terminus and one or several WW domains ( see Chapter 8.2.6). 

Fig. 2.17. Degradation of the tumor suppressor protein p53 by the ubiquitin-proteosome system. The oncoprotein E6 of the human papilloma virus (HPV) forms a specific complex with the p53 protein and can thus induce the degradation of p53. The E6-p53 complex is recognized by E6-AP, a E3 enzyme of the ubiquitin pathway, as a target protein, whereby a ubiquitin residue is transferred to a lysine residue of p53. In this process, the E6 protein serves as the recognition element for ubiquitin hgation of p53.

The great importance of PtdIns(3,4,5)P3 metabolism for growth regulation is illustrated by the observation that an enzyme of PtdIns(3,4,5)P3 metabolism has been identified as a tumor suppressor protein (Wu et al., 1998). PTEN tumor suppressor protein has lipid phosphatase activity that is specific for hydrolysis of PtdIns(3,4,5)P3. It is assumed that PTEN lipid phosphatase is a negative regulator of the Akt pathway by lowering the concentration of PtdIns(3,4,5)P3 and counteracting stimulation of Akt kinase. 

Surprisingly, a growth inhibiting and pro-apoptotic function has been demonstrated for oncogenic Ras mutants. In primary cell cultures, activation of the Ras pathway is linked to an increase in the concentration of the tumor suppressor proteins p53 and pl9ARF (Serrano, 1997), which both promote programmed cell death, or apoptosis (see Chapter 15). This example shows that, according to the cellular context, the Ras protein can promote both cell death and cell survival via interactions with distinct effector proteins. 

Fig. 13.10. Regulation and attack points of inhibitors of cyclin-dependent protein kinases (CKIs) in mammals. The various CKIs are activated and regulated by different signals. Inhibitory activity of the CKIs is specific for the different CDKs and CDK-cyclin combinations. p53 tumor suppressor protein p53 TGPP transforming growth factor P pRb tumor suppressor protein pRb p21 p2icipi. p27- pl6 pl6 ° CDK cyclin-dependent protein kinase Cyc cyclin E2F trans-...

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