Using functional magnetic resonance imaging (fMRI) we have evaluated the anatomical location of the motor hand area. The segment of the precentral gyrus that most often contained motor hand function was a knob-like structure, that is shaped like an omega or epsilon in the axial plane and like a hook in the sagittal plane. On the cortical surface of cadaver specimens this precentral knob corresponded precisely to the characteristic 'middle knee' of the central sulcus that has been described by various anatomists in the last century. We were then able to show that this knob is a reliable landmark for identifying the precentral gyrus directly. We therefore conclude that neural elements involved in motor hand function are located in a characteristic 'precentral knob' which is a reliable landmark for identifying the precentral gyrus under normal and pathological conditions. It faces and forms the 'middle knee' of the central sulcus, is located just at the cross point between the precentral sulcus and the central sulcus, and is therefore also visible on the cortical surface.

The activity of the p53 tumor suppressor protein and the c-Jun protooncogene is regulated by posttranslational modifications, such as phosphorylation or ubiquitination. In addition, covalent attachment of the ubiquitin-like modifier SUMO appears to modulate their transcriptional activity. Sumoylation proceeds via an enzymatic pathway that is mechanistically analogous to ubiquitination, but requires a different E1-activating enzyme and Ubc9, a SUMO-specific E2-conjugating enzyme. Here, we show that two members of the PIAS family, PIAS1 and PIASx␤, act as specific E3-like ligases that promote sumoylation of p53 and c-Jun in vitro and in vivo. The PIAS proteins physically interact with both p53 and c-Jun. In addition, they bind to Ubc9, suggesting that they recruit the E2 enzyme to their respective substrate. The SUMO ligase activity requires the conserved zinc-finger domain, which is distantly related to the essential RING-finger motif, found in a subset of ubiquitin ligases. Furthermore, similar to RING-type ubiquitin ligases, PIASx␤ can catalyze its own modification. Hence, these data further extend the analogy between the ubiquitin and SUMO pathway. Strikingly, PIAS proteins strongly repress the transcriptional activity of p53, suggesting that the PIAS-SUMO pathway plays a crucial role in the regulation of p53 and presumably other transcription factors. Many cellular key functions are regulated by the covalent modification of proteins with the ubiquitin-like SUMO-1 modifier (1-3). Two important examples are the transcriptional activity of the c-Jun protooncogene and the p53 tumor suppressor, which seem to be regulated by sumoylation (4-6). Mammalian SUMO-1 and its close relatives, SUMO-2 and SUMO-3, are about 18% identical to ubiquitin and are conjugated via an enzymatic cascade that requires a SUMO-specific, heterodimeric E1-activating enzyme (Aos1͞Uba2) and a single E2-type conjugating enzyme, Ubc9. In the ubiquitin pathway, at least one additional factor, called E3 or ubiquitin ligase, is required for substrate recognition and formation of an isopeptide bond between ubiquitin and the target protein. Because the SUMO-specific E2 enzyme Ubc9 has been shown to physically interact with almost all known SUMO substrates in yeast twohybrid assays, Ubc9 was considered to be sufficient for substrate recognition.Very recently, however, in the yeast Saccharomyces cerevisiae, the Siz1 and Siz2 proteins were identified as E3-like factors that promote SUMO conjugation to yeast proteins, in particular to proteins of the septin family (7-9). Siz proteins are homologous to members of the mammalian PIAS (protein inhibitor of activated Stat) family of proteins. In humans, this family consists of at least five members: PIAS1, PIAS3, the ␣ and ␤ splice variants of PIASx, and PIASy (10). PIAS proteins were initially identified as specific inhibitors of Stat transcription factors. PIAS1 and PIAS3 block the DNA binding activity of activated Stat1 and Stat3, respectively, and inhibit Stat-mediated transcription (11, 12). Subsequentl...

Post-translational modification with the ubiquitin-like SUMO protein is involved in the regulation of many cellular key processes. The SUMO system modulates signal transduction pathways, including cytokine, Wnt, growth factor and steroid hormone signalling. SUMO frequently restrains the activity of downstream transcription factors in these pathways presumably by facilitating the recruitment of corepressors or mediating the assembly of repressor complexes. Additionally, evidence is accumulating that SUMO controls pathways important for the surveillance of genome integrity. SUMO regulates the PML/p53 tumour suppressor network, a key determinant in the cellular response to DNA damage. Moreover, proteins that maintain genomic stability by functioning at the interface between DNA replication, recombination and repair processes undergo SUMOylation. We will discuss some key findings that exemplify the role of SUMO in transcriptional regulation and genome surveillance.

Protein inhibitor of activated STATs (PIAS) proteins were initially identified as negative regulators of cytokine signalling that inhibit the activity of STAT-transcription factors. Evidence is accumulating that PIAS proteins function as transcriptional coregulators in various other important cellular pathways, including Wnt signalling, the p53 pathway and steroid hormone signalling. Most interestingly, recent work from several laboratories revealed that PIAS proteins act as E3-like ligases that stimulate the attachment of the ubiquitin-like SUMO modifier to target proteins acting in these pathways. Since in most cases the SUMO ligase activity and the transcriptional coregulator activity are functionally correlated, the PIAS/SUMO pathway appears to be an important mechanism of transcriptional regulation. In this review we will discuss some key findings that exemplify the role of PIAS proteins in the regulation of transcriptional processes and propose a model how the PIAS/ SUMO system may modulate transcriptional activities by mediating the assembly of coactivator or corepressor complexes within distinct subnuclear structures.

Finally we report that the sumoylation of c-Fos is a dynamic process that can be reversed via multiple mechanisms. This supports the idea that this modification does not constitute a final inactivation step that necessarily precedes protein degradation.

We evaluated the accuracy of PET/CT with 68 Ga-PSMA-HBED-CC-a 68 Ga-conjugated ligand of human prostate-specific membrane antigen (PSMA)-to localize cancer in the prostate and surrounding tissue at initial diagnosis. Methods: Twenty-one patients with biopsy-proven prostate cancer underwent 68 Ga-PSMA-HBED-CC ( 68 Ga-PSMA) PET/CT at a median of 4 d (range, 0-47 d) before radical prostatectomy. Based on a 6-segment model, the Gleason score and proportion of tumor tissue within each segment (segmental tumor burden, or STB) as determined by histopathology (STB HP ) were correlated with SUV max and STB as determined by different SUV cutoffs for 68 Ga-PSMA PET (STB ). Furthermore, the involvement of seminal vesicles and other extracapsular extension were assessed by histopathology and PET/CT. Results: Histopathology-positive segments (n 5 100 of 126; 79%) demonstrated a significantly higher mean ± SD SUV max (11.8 ± 7.6) than histopathology-negative segments (4.9 ± 2.9; P , 0.001). Receiver-operating-characteristic analysis revealed an optimal SUV max cutoff of 6.5 for discrimination of histopathology-positive segments from histopathology-negative segments (area under the curve, 0.84; P , 0.001), which gave 67% sensitivity, 92% specificity, a 97% positive predictive value, a 42% negative predictive value, and 72% accuracy. STB PET3 as determined by (2 · blood SUV) 1 (2 · SD) correlated best with STB HP (Pearson ρ 5 0.68; P , 0.001; mean difference ± SD, 19% ± 15%). PET/CT correctly detected invasion of seminal vesicles (n 5 11 of 21 patients; 52%) with 86% accuracy and tumor spread through the capsule (n 5 12; 57%) with 71% accuracy. Conclusion: 68 Ga-PSMA PET/CT accurately detected the location and extent of primary prostate cancer. Our preliminary findings warrant further investigation of 68 Ga-PSMA PET/CT in conjunction with needle biopsy.

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Identification of the cortical area responsible for motor hand function was similar with functional MR imaging and with direct stimulation at surgery. A space-occupying lesion can change the cortical representation of motor hand function.