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Identification of Piwil2-like (PL2L) proteins that promote tumorigenesis.

Ye Y, Yin DT, Chen L, Zhou Q, Shen R, He G, Yan Q, Tong Z, Issekutz AC, Shapiro CL, Barsky SH, Lin H, Li JJ, Gao JX - PLoS ONE (2010)

Bottom Line: Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers.Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB.These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, United States of America.

ABSTRACT
PIWIL2, a member of PIWI/AGO gene family, is expressed in the germline stem cells (GSCs) of testis for gametogenesis but not in adult somatic and stem cells. It has been implicated to play an important role in tumor development. We have previously reported that precancerous stem cells (pCSCs) constitutively express Piwil2 transcripts to promote their proliferation. Here we show that these transcripts de facto represent Piwil2-like (PL2L) proteins. We have identified several PL2L proteins including PL2L80, PL2L60, PL2L50 and PL2L40, using combined methods of Gene-Exon-Mapping Reverse Transcription Polymerase Chain Reaction (GEM RT-PCR), bioinformatics and a group of novel monoclonal antibodies. Among them, PL2L60 rather than Piwil2 and other PL2L proteins is predominantly expressed in various types of human and mouse tumor cells. It promotes tumor cell survival and proliferation in vitro through up-regulation of Stat3 and Bcl2 gene expressions, the cell cycle entry from G(0/1) into S-phase, and the nuclear expression of NF-κB, which contribute to the tumorigenicity of tumor cells in vivo. Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers. Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB. These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction. The identification of PL2L proteins provides a novel insight into the mechanisms of cancer development as well as a novel bridge linking cancer diagnostics and anticancer drug development.

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The hypothetical mechanisms underlying PL2L60 promoting tumorigenesis.PL2L60 can promote tumor cell growth through interaction with NF-κB. Migration of PL2L60 from cytoplasm to nucleus may promote nuclear localization of NF-κB. In the nucleus, PL2L60 might promote the transcriptional activity of NF-κB through remodeling chromatin structure, resulting in enhanced transcription of genes for cell survival, cell cycling and cell growth. This model might lead us to identification of novel signaling pathways specific for tumor cell survival and proliferation.
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pone-0013406-g009: The hypothetical mechanisms underlying PL2L60 promoting tumorigenesis.PL2L60 can promote tumor cell growth through interaction with NF-κB. Migration of PL2L60 from cytoplasm to nucleus may promote nuclear localization of NF-κB. In the nucleus, PL2L60 might promote the transcriptional activity of NF-κB through remodeling chromatin structure, resulting in enhanced transcription of genes for cell survival, cell cycling and cell growth. This model might lead us to identification of novel signaling pathways specific for tumor cell survival and proliferation.

Mentions: Obviously, PL2L60 is not limited to be expressed in pCSCs [5]. It was also detected in various types of cancer cell lines. Knockdown of PL2L60 mRNAs in murine pCSCs or human breast cancer cells significantly suppressed their expansion in vitro. In agreement, over-expression of PL2L60 in the breast cancer cell lines led to their increased expansion in vitro. The mechanisms underlying the increased expansion appear to be mediated by reduced programmed cell death (PCD) because of enhanced expression of Bcl-2 and Stat3 genes and promoted G0/1 → S-phase in cell cycle by PL2L60. This is further supported by the increased expression of nuclear NF-κB in the PL2L60-transduced cell lines. NF-κB is a ubiquitous transcription factor that controls the expression of genes involved in immune response, cell survival, apoptosis, and cell cycle. Given the fact that NF-κB is inactivated in cytosol complexed with the inhibitory protein IκBα but activated by ubiquitination of IκBα, shuttling to nucleus, only is nuclear NF-κB considered to be functional [45], [46]. Nuclear translocation of NF-κB may up-regulate prosurvival factor Bcl-2 in tumor cells, as observed in human hepatoma cells [52]. Thus, the increased nuclear NF-κB expression in the nuclei of PL2L60-transduced cells may lead to increased cell expansion through up-regulating cell survival genes Stat-3 and Bcl-2 and promoting cell cycling (Fig. 9).


Identification of Piwil2-like (PL2L) proteins that promote tumorigenesis.

Ye Y, Yin DT, Chen L, Zhou Q, Shen R, He G, Yan Q, Tong Z, Issekutz AC, Shapiro CL, Barsky SH, Lin H, Li JJ, Gao JX - PLoS ONE (2010)

The hypothetical mechanisms underlying PL2L60 promoting tumorigenesis.PL2L60 can promote tumor cell growth through interaction with NF-κB. Migration of PL2L60 from cytoplasm to nucleus may promote nuclear localization of NF-κB. In the nucleus, PL2L60 might promote the transcriptional activity of NF-κB through remodeling chromatin structure, resulting in enhanced transcription of genes for cell survival, cell cycling and cell growth. This model might lead us to identification of novel signaling pathways specific for tumor cell survival and proliferation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2958115&req=5

pone-0013406-g009: The hypothetical mechanisms underlying PL2L60 promoting tumorigenesis.PL2L60 can promote tumor cell growth through interaction with NF-κB. Migration of PL2L60 from cytoplasm to nucleus may promote nuclear localization of NF-κB. In the nucleus, PL2L60 might promote the transcriptional activity of NF-κB through remodeling chromatin structure, resulting in enhanced transcription of genes for cell survival, cell cycling and cell growth. This model might lead us to identification of novel signaling pathways specific for tumor cell survival and proliferation.
Mentions: Obviously, PL2L60 is not limited to be expressed in pCSCs [5]. It was also detected in various types of cancer cell lines. Knockdown of PL2L60 mRNAs in murine pCSCs or human breast cancer cells significantly suppressed their expansion in vitro. In agreement, over-expression of PL2L60 in the breast cancer cell lines led to their increased expansion in vitro. The mechanisms underlying the increased expansion appear to be mediated by reduced programmed cell death (PCD) because of enhanced expression of Bcl-2 and Stat3 genes and promoted G0/1 → S-phase in cell cycle by PL2L60. This is further supported by the increased expression of nuclear NF-κB in the PL2L60-transduced cell lines. NF-κB is a ubiquitous transcription factor that controls the expression of genes involved in immune response, cell survival, apoptosis, and cell cycle. Given the fact that NF-κB is inactivated in cytosol complexed with the inhibitory protein IκBα but activated by ubiquitination of IκBα, shuttling to nucleus, only is nuclear NF-κB considered to be functional [45], [46]. Nuclear translocation of NF-κB may up-regulate prosurvival factor Bcl-2 in tumor cells, as observed in human hepatoma cells [52]. Thus, the increased nuclear NF-κB expression in the nuclei of PL2L60-transduced cells may lead to increased cell expansion through up-regulating cell survival genes Stat-3 and Bcl-2 and promoting cell cycling (Fig. 9).

Bottom Line: Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers.Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB.These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, United States of America.

ABSTRACT
PIWIL2, a member of PIWI/AGO gene family, is expressed in the germline stem cells (GSCs) of testis for gametogenesis but not in adult somatic and stem cells. It has been implicated to play an important role in tumor development. We have previously reported that precancerous stem cells (pCSCs) constitutively express Piwil2 transcripts to promote their proliferation. Here we show that these transcripts de facto represent Piwil2-like (PL2L) proteins. We have identified several PL2L proteins including PL2L80, PL2L60, PL2L50 and PL2L40, using combined methods of Gene-Exon-Mapping Reverse Transcription Polymerase Chain Reaction (GEM RT-PCR), bioinformatics and a group of novel monoclonal antibodies. Among them, PL2L60 rather than Piwil2 and other PL2L proteins is predominantly expressed in various types of human and mouse tumor cells. It promotes tumor cell survival and proliferation in vitro through up-regulation of Stat3 and Bcl2 gene expressions, the cell cycle entry from G(0/1) into S-phase, and the nuclear expression of NF-κB, which contribute to the tumorigenicity of tumor cells in vivo. Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers. Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB. These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction. The identification of PL2L proteins provides a novel insight into the mechanisms of cancer development as well as a novel bridge linking cancer diagnostics and anticancer drug development.

Show MeSH
Related in: MedlinePlus