Portal de Periódicos da CAPES

Cyclin-like Oscillations in Levels of the Nucleoporin Nup96 Control G1/S Progression

2008; Elsevier BV; Volume: 15; Issue: 5 Linguagem: Inglês

10.1016/j.devcel.2008.10.010

1878-1551

Richard W. Wozniak, David S. Goldfarb,

RNA modifications and cancer

In this issue of Developmental Cell, Chakraborty et al. report that efficient advancement through G1/S phase requires the downregulation of Nup96 levels during M phase. The authors show that oscillations in Nup96 levels plays a key role in maintaining normal cell proliferation, likely by regulating the export of specific mRNAs, including those of key cell cycle regulators. In this issue of Developmental Cell, Chakraborty et al. report that efficient advancement through G1/S phase requires the downregulation of Nup96 levels during M phase. The authors show that oscillations in Nup96 levels plays a key role in maintaining normal cell proliferation, likely by regulating the export of specific mRNAs, including those of key cell cycle regulators. The nuclear pore complex (NPC) catalyzes the transport of macromolecules across the nuclear envelope (NE). There are many examples of gene expression being regulated by controlling the nuclear transport of transcription factors and other signaling molecules. The NPC also serves an important proofreading function by recognizing and exporting only fully processed mRNAs. Many of the ∼30 nucleoporins (nups) that make up the NPC function as membrane coatamers to stabilize the highly curved membrane of the nuclear pore. These nups are organized into several subcomplexes that form the cage-like architectural framework or "annulus" of the NPC. The annulus surrounds the central translocation channel. A major component of the annulus is the Nup107-160 complex, which in vertebrates contains nine nups. In recent years it has become clear that this subcomplex plays key roles in the assembly and structural integrity of NPCs, and in the export of mRNAs (D'Angelo and Hetzer, 2008D'Angelo M.A. Hetzer M.W. Trends Cell Biol. 2008; 18: 456-466Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar). In this issue, Chakraborty and coworkers report that a subunit of this subcomplex, Nup96, is uniquely regulated during the cell cycle (Chakraborty et al., 2008Chakraborty P. Wang Y. Wei J.-H. van Deursen J. Yu H. Malureanu L. Dasso M. Forbes D.J. Levy D.E. Seemann J. Fontoura B.M.A. Dev. Cell. 2008; 15 (this issue): 657-667Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). Changes in the levels Nup96 appear to directly influence cell proliferation by differentially regulating the export of specific mRNAs, including those encoding cell cycle regulators. It is generally assumed that nups are present in the NPC in fixed stoichiometries. The octagonal symmetry of the NPC suggests that each nup is present in some multiple of eight. As cells prepare for mitosis during S and G2 phases of the cell cycle, the number of NPCs doubles. This provides sufficient material for the two nuclei that reassemble in the daughter cells during the latter stages of mitosis. The biogenesis of new NPCs has been assumed to involve the coordinated expression of nups. Surprising, however, Chakraborty et al., 2008Chakraborty P. Wang Y. Wei J.-H. van Deursen J. Yu H. Malureanu L. Dasso M. Forbes D.J. Levy D.E. Seemann J. Fontoura B.M.A. Dev. Cell. 2008; 15 (this issue): 657-667Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar observed that, while other members of the Nup107-160 subcomplex are maintained at consistent levels between S/G2 phase through mitosis, at the onset of M phase a portion of Nup96 was targeted for degradation by the ubiquitin-proteasome pathway. The Nup107-160 subcomplex was known to be recruited to kinetochores during mitosis, where it plays an ill-defined but essential role in progression through mitosis (Zuccolo et al., 2007Zuccolo M. Alves A. Galy V. Bolhy S. Formstecher E. Racine V. Sibarita J.B. Fukagawa T. Shiekhattar R. Yen T. Doye V. EMBO J. 2007; 26: 1853-1864Crossref PubMed Scopus (150) Google Scholar). Thus, it seemed reasonable that the regulated decrease in Nup96 levels might play a role in progression through mitosis. However, conditions that prevented the depletion of Nup96 had little effect on mitosis. Instead, the authors showed that lowering Nup96 levels during mitosis has its effects later in the cell cycle, controlling the rate of progression from G1 to S phase. Accordingly, elevated levels of Nup96 impeded progression through G1 and the G1/S phase transition. Thus cellular levels of Nup96 affect the rate of cell proliferation. T cells derived from Nup96+/− mice, which contain reduced amounts of Nup96, proliferated faster than normal cells. This finding is particularly intriguing when considering that some forms of acute myelogenous leukemia (AML) involve chromosomal translocations that disrupt the NUP98-NUP96 gene (reviewed in Kalverda and Fornerod, 2007Kalverda B. Fornerod M. Dev. Cell. 2007; 13: 164-165Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Nup98 and Nup96 are produced by autoproteolytic cleavage of a Nup98-Nup96 precursor. In many of the AML translocations, the N terminus of Nup98 is fused to the DNA binding domain of a homeodomain transcription factor. These translocations are predicted to disrupt expression of Nup96, which, based on the findings in this report, could contribute to increased cell proliferation. Thus, it is possible that Nup96 is a tumor suppressor. How could changes in the levels of Nup96 control cell proliferation? One potential mechanism would be to alter the expression of cell cycle regulators. As mentioned above, the Nup107-160 complex had been implicated in the control of mRNA export. Specifically, macrophages derived from Nup96+/− mice exhibit a reduction in the export of immune-related genes (Faria et al., 2006Faria A.M. Levay A. Wang Y. Kamphorst A.O. Rosa M.L. Nussenzveig D.R. Balkan W. Chook Y.M. Levy D.E. Fontoura B.M. Immunity. 2006; 24: 295-304Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). The inference of this study was that Nup96 might regulate the export of specific mRNAs. In the current study, Chakraborty et al., 2008Chakraborty P. Wang Y. Wei J.-H. van Deursen J. Yu H. Malureanu L. Dasso M. Forbes D.J. Levy D.E. Seemann J. Fontoura B.M.A. Dev. Cell. 2008; 15 (this issue): 657-667Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar extended this model by studying correlations between Nup96 levels, mRNA export, and proliferation rates of mouse T cells. The authors conclude that the efficiency of export of mRNAs encoding cell cycle regulators is inversely proportional to cellular levels of Nup96. While the depletion of Nup96 levels did not alter total cellular levels of mRNAs encoding the G1 cell cycle regulators Cyclin D3 and CDK6, cytoplasmic levels of these mRNAs were elevated in Nup96+/− T cells, leading to an increase in the production of these proteins and premature entry into S phase. These results suggest that Nup96 might somehow act to suppress the export of these mRNAs. Remarkably, the authors showed that Nup96 might also facilitate the export of other mRNAs during G2 phase in macrophages. Cumulatively, these results support two important conclusions. First, Nup96, and possibly other nups as well, can differentially regulate the export of specific groups of mRNAs. Importantly, this regulatory process can be temporally controlled (e.g., during the cell cycle), perhaps by specific modifications of Nup96. Second, nups can function as both facilitators and inhibitors of nuclear transport. Precedent for such a mechanism has been established for a nuclear import pathway in yeast. Here, Nup53p plays a role in nuclear import during interphase (Marelli et al., 1998Marelli M. Aitchison J.D. Wozniak R.W. J. Cell Biol. 1998; 143: 1813-1830Crossref PubMed Scopus (128) Google Scholar), while in cells arrested in mitosis, changes in the structure of the NPC allow Nup53p to specifically inhibit transport through a cell cycle-specific interaction with a nuclear transport receptor (Makhnevych et al., 2003Makhnevych T. Lusk C.P. Anderson A.M. Aitchison J.D. Wozniak R.W. Cell. 2003; 115: 813-823Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). The study by Chakraborty et al., 2008Chakraborty P. Wang Y. Wei J.-H. van Deursen J. Yu H. Malureanu L. Dasso M. Forbes D.J. Levy D.E. Seemann J. Fontoura B.M.A. Dev. Cell. 2008; 15 (this issue): 657-667Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar raises the question of how variations in the level of a generic subunit of the NPC like Nup96 can differentially affect the export of particular mRNAs. Their results suggest that those mRNAs whose export is regulated by Nup96 are functionally related (e.g., in T cells G1 cell cycle regulators). This raises the possibility that these mRNAs may fall within RNA "regulons" (see Keene, 2007Keene J.D. Nat. Rev. Genet. 2007; 8: 533-543Crossref PubMed Scopus (945) Google Scholar) and that specific trans-acting factors control their nuclear export. Seminal studies in yeast (Saavedra et al., 1997Saavedra C.A. Hammell C.M. Heath C.V. Cole C.N. Genes Dev. 1997; 11: 2845-2856Crossref PubMed Scopus (111) Google Scholar) and, more recently, in Drosophila (Farny et al., 2008Farny N.G. Hurt J.A. Silver P.A. Genes Dev. 2008; 22: 66-78Crossref PubMed Scopus (60) Google Scholar) highlight the potential diversity of the nuclear export machinery and thus admit the possibility that distinct subsets of functionally related mRNAs (presumably through trans-acting factors) utilize specific arms of the export machinery. Nup96 could regulate the export of specific groups of mRNA by modulating the interaction of mRNA export factors with the NPC. Yet another exciting possibility is that Nup96 itself functions as a specific mRNA trans-acting factor. Nup96 is one of a handful of nups that are present both at the NPC and within an intranuclear pool (Fontoura et al., 1999Fontoura B.M. Blobel G. Matunis M.J. J. Cell Biol. 1999; 144: 1097-1112Crossref PubMed Scopus (185) Google Scholar). The intranuclear function of Nup96 is not known; however, the existence of a nucleoplasmic pool raises the possibly that Nup96 exerts control on mRNA export through a direct interaction with mRNPs at a point prior to its association with the NPC. It will be fascinating to learn if the novel role that levels of Nup96 play in cell proliferation is due to an effect on the structure and function of the NPC proper or secondary functions of its intranuclear pool. Nucleoporin Levels Regulate Cell Cycle Progression and Phase-Specific Gene ExpressionChakraborty et al.Developmental CellNovember 11, 2008In BriefThe Nup107-160 complex, the largest subunit of the nuclear pore, is multifunctional. It mediates mRNA export in interphase, and has roles in kinetochore function, spindle assembly, and postmitotic nuclear pore assembly. We report here that the levels of constituents of the Nup107-160 complex are coordinately cell cycle-regulated. At mitosis, however, a member of the complex, Nup96, is preferentially downregulated. This occurs via the ubiquitin-proteasome pathway. When the levels of Nup96 are kept high, a significant delay in G1/S progression occurs. Full-Text PDF Open Archive