Oncogene database

4515

MTCP1

mature T-cell proliferation 1;MTCP1;mature T-cell proliferation 1

MTCP-1 type B1|mature T-cell proliferation 1 isoform p13|mature T-cell proliferation-1 type B1|protein p13 MTCP-1

Xq28

protein-coding

The equilibrium and kinetic folding properties of a small oncogene product, P13(MTCP1), of novel topology have been investigated using perturbation by guanidine hydrochloride and observation by fluorescence, circular dichroism and two-dimensional heteronuclear NMR spectroscopy. The structure of P13(MTCP1) is comprised of a canonical filled beta-barrel, although the topology of the structure is absolutely unique, rendering the folding properties of this protein of great interest. Equilibrium measurements of the intrinsic fluorescence emission spectrum, the fluorescence decay, the circular dichroism spectrum and the (15)N-(1)H heteronuclear single quantum coherence (HSQC) correlation spectrum as a function of increasing concentrations of denaturant showed no evidence for the population of any equilibrium intermediates, although negative amplitudes on the blue edge of the tryptophan emission and loss of intensity of the native HSQC correlation peaks were indicative of increased conformational dynamics at low denaturant concentrations. The free energy and cooperativity of unfolding as observed by fluorescence and circular dichroism were in relatively good agreement, also consistent with a two-state transition. Kinetics measurements of the fluorescence emission as a function of denaturant concentration revealed that P13(MTCP1) is the slowest folding beta-structure protein reported to date. Comparison of the activation cooperativity values (m(f) and m(u)) indicates that the structure of the transition state is quite close to the folded state in terms of exposed surface area. The calculated contact order of P13(MTCP1) is relatively low and does not appear to explain its slow rate of folding. We suggest that the complex topology of this protein, which would require the ordering of the beta-barrel through a long loop joining the two L-shaped components of the barrel, could provide an explanation for this slow folding.

The E2F family of transcription factors is essential in the regulation of the cell cycle and apoptosis. While the activity of E2F1-3 is tightly controlled by the retinoblastoma family of proteins, the expression of these factors is also regulated at the level of transcription, post-translational modifications and protein stability. Recently, a new level of regulation of E2Fs has been identified, where micro-RNAs (miRNAs) from the mir-17-92 cluster influence the translation of the E2F1 mRNA. We now report that miR-20a, a member of the mir-17-92 cluster, modulates the translation of the E2F2 and E2F3 mRNAs via binding sites in their 3 -untranslated region. We also found that the endogenous E2F1, E2F2, and E2F3 directly bind the promoter of the mir-17-92 cluster activating its transcription, suggesting an autoregulatory feedback loop between E2F factors and miRNAs from the mir-17-92 cluster. Our data also point toward an anti-apoptotic role for miR-20a, since overexpression of this miRNA decreased apoptosis in a prostate cancer cell line, while inhibition of miR-20a by an antisense oligonucleotide resulted in increased cell death after doxorubicin treatment. This anti-apoptotic role of miR-20a may explain some of the oncogenic capacities of the mir-17-92 cluster. Altogether, these results suggest that the autoregulation between E2F1-3 and miR-20a is important for preventing an abnormal accumulation of E2F1-3 and may play a role in the regulation of cellular proliferation and apoptosis.

The human oncoprotein p13MTCP1 is coded by the MTCP1 gene, a gene involved in chromosomal translocations associated with T-cell prolymphocytic leukemia, a rare form of human leukemia with a mature T-cell phenotype. The primary sequence of p13MTCP1 is highly and only homologous to that of p14TCL1, a product coded by the gene TCL1 which is also involved in T-cell prolymphocytic leukemia. These two proteins probably represent the first members of a new family of oncogenic proteins. We present the three-dimensional solution structure of the recombinant p13MTCP1 determined by homonuclear proton two-dimensional NMR methods at 600 MHz. After proton resonance assignments, a total of 1253 distance restraints and 64 dihedral restraints were collected. The solution structure of p13MTCP1 is presented as a set of 20 DYANA structures. The rmsd values with respect to the mean structure for the backbone and ALL heavy atoms for the conformer family are 1.07 +/- 0.19 and 1.71 +/- 0.17 A, when the structured core of the protein (residues 11-103) is considered. The solution structure of p13MTCP1 consists of an orthogonal beta-barrel, composed of eight antiparallel beta-strands which present an original arrangement. The two beta-pleated loops which emerge from this barrel might constitute the interaction surface with a potential molecular partner.