Human MCRS2, a cell-cycle-dependent protein, associates with LPTS/PinX1 and reduces the telomere length

Song, Hai; Li, Yiliang; Chen, Guoyuan; Xing, Zhen; Zhao, Jing; Yokoyama, Kazunari K.; Li, Tsaiping; Zhao, Ming

doi:10.1016/j.bbrc.2004.02.166

Cited by 36 publications

(40 citation statements)

References 33 publications

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“…MSP58's ability to transform cells seems contrary to a previous report that MSP58 and MCRS2 inhibit telomerase activity (9). However, dephosphorylation of Akt significantly reduces telomerase activity and induces apoptosis (18).…”

Section: Discussioncontrasting

confidence: 51%

“…ICP22 is a regulatory protein from herpes simplex virus 1 (10); p120 is a proliferation-related protein expressed at high levels in most human malignant tumor cells (11); and Daxx is a transcriptional repressor and signal transducer for Fas (16). MCRS2, a splice variant of MSP58͞MCRS1, binds the Pin2͞TRF1 telomere protein and the catalytic hTERT subunit of telomerase (9). Toj3, an MSP58 orthologue, functions downstream of v-jun to transform quail embryo fibroblast (QEF) and chicken embryo fibroblast (CEF) cells (11).…”

Section: Discussionmentioning

confidence: 99%

“…Immunof luorescence with PTEN and MSP58 was performed with mouse monoclonal PTEN (CascadeBioscience, Winchester, MA) and rabbit polyclonal MSP58 antibodies (9). MEFs were fixed for 30 min in 4% paraformaldehyde, incubated for 1 h with anti-PTEN and MSP58 antibodies and then with anti-mouse IgG Alexa Fluor 488 and anti-rabbit IgG 568 secondary antibodies (Molecular Probes), and viewed with a Nikon microscope equipped with a Hamamatsu ORCA-ER camera controlled by METAMORPH software (Universal Imaging, Downingtown, PA).…”

Section: Methodsmentioning

confidence: 99%

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Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor

Okumura

Zhao

DePinho

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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106

103

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The PTEN (phosphatase and tensin homologue) tumor suppressor protein contains a single catalytic domain with both lipid and protein phosphatase activities. The remaining C-terminal half of the PTEN protein plays a role in its stability and is mutated in many clinical cancer samples. Here, we report that the PTEN C-terminal domain physically interacts with the forkhead-associated domain of the oncogenic MSP58 protein and that this interaction requires PTEN Thr-366. We further show that while MSP58 transforms Pten؊͞؊ mouse embryo fibroblasts (MEFs), concurrent introduction of wild-type PTEN causes a dramatic reduction in the number of MSP58-induced transformed foci. This PTEN-mediated inhibition of cellular transformation requires physical interaction as evidenced by the failure of PTEN(T366A) point mutation (residing within the MSP58 interaction domain) to suppress MSP-58-driven transformation. These observations, together with the capacity of catalytically inactive PTEN mutant (G129R) to suppress MSP58 oncogenicity, support the view that the C-terminal region of PTEN directly provides a previously uncharacterized biological function in its ability to regulate cellular transformation. P TEN (phosphatase and tensin homology, deleted on chromosome ten) is a tumor suppressor gene that is frequently somatically deleted or mutated in a variety of human cancers including those of the brain, endometrium, prostate, and lung (1, 2). Germ-line mutations of PTEN are also the cause of Cowden's disease, an autosomal dominant hamartoma syndrome with increased risk for the development of tumors in a variety of tissues (1, 2).PTEN dephosphorylates the 3Ј position of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] and phosphatidylinositol 3,4-bisphosphate [PI(3,4)P 2 ] and tyrosine-phosphorylated FAK and Shc. These activities inhibit cell growth and cell migration, respectively (3). The PTEN protein consists of an N-terminal phosphatase domain and a C-terminal domain, which is subdivided into C2, phosphorylation, and PDZ (PSD-95, disc-large, Zonula Occludens-1) binding domains (1). Sequencing of the PTEN gene in spontaneous tumors, and those arising in genetically predisposed individuals, has shown that Ϸ20% of all known PTEN mutations, including a number of frameshift, nonsense, and missense mutations, target the C-terminal region (2). These data suggest that this region of the PTEN protein may have biological functions distinct from those mediated by its catalytic domain.The C-terminal domain is phosphorylated in vivo, and this phosphorylation regulates PTEN stability and activity (4). However, the physiologically relevant function of PTEN phosphorylation, other than control of protein stability, continues to be an area of active investigation. Within the C-terminal region, the C2 domain has been shown to regulate the activity and stability of the PTEN protein by binding to the plasma membrane and contributing to the proper orientation of its phosphatase domain (5). The C2 domain can also regulate cell migration, indep...

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor

Okumura

Zhao

DePinho

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

103

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“…For example, p78 can induce anchorage-independent growth (Bader et al, 2001;Okumura et al, 2005). In addition, expression of p78 appears to fluctuate throughout the cell cycle (Bruni and Roizman, 1998;Song et al, 2004). Furthermore, a number of earlier studies indicated that p78 can interact with proteins that are involved in oncogenesis, such as the v-Jun oncoprotein and the telomerase-inhibitory protein LPTS/PinX1 (Bader et al, 2001;Song et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

p78/MCRS1 forms a complex with centrosomal protein Nde1 and is essential for cell viability

et al. 2006

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The centrosome, an organelle that functions as the major microtubule-organizing center, plays an essential role in the formation of the mitotic spindle and guiding accurate chromosome segregation. Centrosome aberrations are frequently associated with various forms of human cancers and it is thought that defects in this organelle contribute to genomic instability and malignant transformation. We recently identified and characterized a centrosome-localized protein complex that is comprised of Su48 and Nde1. Disruption of the normal function of these proteins leads to abnormal cell division. To extend our understanding of how this protein complex operates, we sought to identify Nde1-interacting molecules by the yeast two-hybrid screening method. Here, we demonstrate that both Nde1 and Su48 can associate with p78/MCRS1, a protein implicated in cancer development. We found that, whereas the majority of p78 localizes to the nucleus as reported in earlier studies, a fraction of the p78 protein can be detected in the centrosome. Moreover, we determined that a region containing the forkhead-associated domain of p78 is involved in association with Nde1 and Su48, as well as in centrosomal localization. We also provide evidence that the association between p78 and Nde1 is regulated by phosphorylation on Nde1. Furthermore, abrogation of the endogenous p78 function by small interfering RNA knockdown causes cell death and a modest delay in mitosis. These results indicate that a subset of the p78 proteins comprises a component of the centrosome and that p78 is essential for cell viability.

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“…It has also been shown that MCRS1 can relieve the repressor activity of Daxx, an adaptor protein that links Fas signaling to the c-Jun NH 2 -terminal kinase pathway via a nucleolar sequestration mechanism (39). MCRS2 is involved in telomere shortening by associating with telomerase (37). In addition, binding and stabilization of MSP58 by transcription factor STRA13 has been observed (40).…”

mentioning

confidence: 99%

Microspherule Protein 1, Mi-2β, and RET Finger Protein Associate in the Nucleolus and Up-regulate Ribosomal Gene Transcription

Shimono

Shimokata

et al. 2005

Journal of Biological Chemistry

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The nucleolus is the site of ribosomal DNA (rDNA) transcription and ribosome production. In exploring the role of nucleolar protein MCRS1 (microspherule protein1)/MSP58 (58-kDa microspherule protein), we found that Mi-2␤, a component of a nucleosome remodeling and deacetylase (NuRD) complex, RET finger protein (RFP), and upstream binding factor (UBF) were associated with MCRS1. Yeast two-hybrid assays revealed that MCRS1 bound to the ATPase/helicase region of Mi-2␤ and the coiled-coil region of RFP. Interestingly, confocal microscopic analyses revealed the co-localization of MCRS1, Mi-2␤, RFP, and the rRNA transcription factor UBF in the nucleoli. We also found that MCRS1, Mi-2␤, and RFP were associated with rDNA using a chromatin immunoprecipitation assay. Finally, we showed that MCRS1, Mi-2␤, and RFP up-regulated transcriptional activity of the rDNA promoter and that ribosomal RNA transcription was repressed when MCRS1, Mi-2␤, and RFP expression was reduced using siRNA. These results indicated that Mi-2␤ and RFP, known to be involved in transcriptional repression in the nucleus, co-localize with MCRS1 in the nucleolus and appear to activate the rRNA transcription.

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Human MCRS2, a cell-cycle-dependent protein, associates with LPTS/PinX1 and reduces the telomere length

Cited by 36 publications

References 33 publications

Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor

Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor

p78/MCRS1 forms a complex with centrosomal protein Nde1 and is essential for cell viability

Microspherule Protein 1, Mi-2β, and RET Finger Protein Associate in the Nucleolus and Up-regulate Ribosomal Gene Transcription

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