Disease relevance of PCM1

• PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation [1].
• A translocation generating the constitutively activated fusion protein PCM1-JAK2 has also been recently found in atypical chronic myelogenous leukemia and acute leukemia [2].
• A t(8;9) translocation with PCM1-JAK2 fusion in a patient with T-cell lymphoma [3].
• Three genes (FLJ32642, MTSG1, and PCM1) had a significantly (P< 0.001, P< 0.004, and P< 0.001) lower expression in primary ovarian carcinoma compared with controls (ovarian tissues and cysts) [4].
• Breast tumor centrosomes display characteristic structural abnormalities, termed centrosome amplification , including: increase in centrosome number and volume, accumulation of excess pericentriolar material, supernumerary centrioles, and inappropriate phosphorylation of centrosome proteins [5].

High impact information on PCM1

• Here we show that BBS4 localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery to recruit PCM1 (pericentriolar material 1 protein) and its associated cargo to the satellites [6].
• A polyclonal antibody raised against the protein was able to 'supershift' the native MeCP11 complex from HeLa cells, indicating that PCM1 is a component of mammalian MeCP1 [7].
• Electron microscopic immunocytochemistry localized this antigen in dense pericentriolar material (PCM) surrounding the centrioles [8].
• The centrosome consists of a pair of centrioles and a surrounding matrix of pericentriolar material that anchors microtubule nucleation sites and consequently determines the number and organization of microtubules in interphase and mitotic cells [9].
• Here, we identify a novel centrosomal substrate of Plk1, Kizuna (Kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles [10].
• PCM1 has sense Alu elements in its 3'UTR region, making it susceptible to the regulation of other protein-coding or non-coding RNAs with antisense Alu elements [11].

Biological context of PCM1

• The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene [12].
• Mapping of the human autoantigen pericentriolar material 1 (PCM1) gene to chromosome 8p21.3-p22 [13].
• Patients with PCM1-JAK2 disease are attractive candidates for targeted signal transduction therapy [14].
• Gc subtypes of 20 North and Central American populations and PCM1 subtypes in 11 populations were analyzed to identify interpopulation variation of the respective gene frequencies for common alleles [15].
• These results demonstrate that the pericentriolar material is a dynamic substance whose composition can fluctuate during the cell cycle [16].

Anatomical context of PCM1

• In cells, BBS8 localizes to centrosomes and basal bodies and interacts with PCM1, a protein probably involved in ciliogenesis [17].
• Immunodepletion of neither pericentrin-B nor PCM-1 from cellular extracts inhibited the ability of salt-stripped centrosomes to recover microtubule nucleation potential, demonstrating that neither protein plays a key role in microtubule nucleation processes [18].
• By 24 h, centrioles have formed inside of already well-developed PCM clouds [19].
• Immunohistochemistry, using an antibody specific for the C-terminal portion of PCM-1 showed that the protein level is drastically decreased and its subcellular localization is altered in thyroid tumor tissue with respect to normal thyroid [20].
• In oocytes, the PCM was found not only at the poles of the barrel-shaped metaphase II spindle but also at many discrete loci around the cytoplasm near the cell cortex [21].

Associations of PCM1 with chemical compounds

• The breakpoints were variable in both genes, but in all cases the chimeric mRNA is predicted to encode a protein that retains several of the predicted coiled-coil domains from PCM1 and the entire tyrosine kinase domain of JAK2 [14].
• The polysaccharide fractions also existed in conformations including random coil (as in PCM0 and PCM1) and expanded chain (as in PCM3), and differed molecular mass [22].
• Although clouds of PCM consistently form even when microtubules are completely disassembled by nocodazole, the centrioles are not assembled under these conditions [19].
• Conversely, cells arrested at the G1/S boundary of the cell cycle maintained PCM-1 mRNA at artificially elevated levels, providing a possible molecular mechanism for explaining the multiple rounds of centrosome replication that occurred in CHO cells during prolonged hydroxyurea-induced arrest [23].
• Stepwise solubilization of centrosomal structures using urea showed that high urea concentrations were required to solubilize centrosomal vinculin, suggesting tight association of vinculin with the pericentriolar material [24].

Other interactions of PCM1

• Dynamic recruitment of Nek2 kinase to the centrosome involves microtubules, PCM-1, and localized proteasomal degradation [25].
• RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma [20].
• FPLC analysis demonstrates that EVI5 protein can form dimers and confocal microscopy indicates that EVI5, in addition to a diffuse localization in the nucleus, also preferentially localizes to the pericentriolar material in interphase cells [26].
• The human autoantibody #5051, which stains the pericentriolar material, colocalizes with PPX antibodies, suggesting that PPX may play a role in microtubule nucleation [27].
• As others have shown that excess pericentriolar material strongly associates with abnormal mitoses, we modeled centrosomal abnormalities with exogenous RHAMM overexpression [28].

Analytical, diagnostic and therapeutic context of PCM1

• By RT-PCR, we confirmed the fusion of 3' part of JAK2 with the 5' part of PCM1 [12].
• Reverse transcription-PCR and fluorescence in situ hybridization confirmed the fusion in this case and also identified PCM1-JAK2 in the six other t(8;9) patients [14].
• A combination of RT - PCR and RACE analyses finally led to the identification of the fusion gene, which involves the 5' portion of PCM-1, a gene coding for a centrosomal protein with distinct cell cycle distribution, and the RET tyrosine kinase (TK) domain [20].
• Immunoelectron microscopy revealed a heat-induced increase in the electron-dense material comprising the pericentriolar material (PCM), consistent with protein aggregation [29].
• Electron microscopy colocalization suggests that binding occurs at the outer boundary of the pericentriolar material [30].

References