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RESEARCH |
1 C S Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Hutzel Hospital, Wayne State University School of Medicine, 2 Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 3 Karmanos Cancer Institute, Wayne State University School of Medicine and 4 Insitute for Environmental Health Science, Wayne State University School of Medicine, Detroit, Michigan 48201, USA and 5 Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, Academic Hospital Groningen, Groningen, The Netherlands
Correspondence should be addressed to Daniel A Rappolee, C S Mott Center for Human Growth and Development, Wayne State University School of Medicine, 275 East Hancock, Detroit, Michigan 48201, USA; Email: drappole{at}med.wayne.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Many investigations on the roles of serine-threonine kinases and transcription factors in mitosis have been carried out in mammalian somatic cells, but little has been done in preimplantation embryos. G1-S phase mitogenic signal transduction is largely mediated by protein kinases; examples include the Raf family, the mitogen activated protein kinase (MAPK) family, the MAPK activating kinase (MEK) family (Roovers & Assoian 2000, Wilkinson & Millar 2000) and transcription factors (e.g. MycC, fos; Sears & Nevins 2002). These transcription factors are downstream of receptor tyrosine kinases (RTK) such as the fibroblast growth factor (FGF) receptor family that mediate a necessary mitogenic input into placental trophoblasts in the preimplantation mouse embryo (Chai et al. 1998). During this important period of decision-making, only small sub-populations of protein kinases may be phosphorylated and perform downstream functions. However, elevated (putatively quantitative) conversion of populations of protein kinases and transcription factors has been observed during late G2, and throughout M phase in somatic cells (Willard & Crouch 2001). Western blotting was used to determine that some serine-threonine kinases were hyper-phosphorylated at M phase in the first two cell divisions of the mouse embryo, but later preimplantation cell divisions showed no hyper-phosphorylation (Iwamori et al. 2000).
The unique role of kinases during M phase is intriguing, but not totally understood. It is likely that (1) there is a change in the substrate range of kinases during M phase, (2) the change must happen quickly due to the short duration of mitosis, and (3) a great number of M phase structural molecules (such as cytoskeletal tubulin) must be phosphorylated. It is likely that nearly 100% of kinases of one type may be converted for about 1 h of mitosis, but less than 10% are converted for a few hours of G1 preceding S phase (Whitmarsh & Davis 1999, 2000, Willard & Crouch 2001). It is therefore important to know about the kinases and transcription factors that are used by the pre-implantation embryo for M phase, if correct interpretations about function at the G1-S phase are to be made.
The purpose of this study was to investigate the expression of activated phosphorylated serine-threonine kinases and transcription factors during mitosis in mouse preimplantation embryos and mouse and human trophoblast cells.
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Materials and Methods |
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all forms (SC7131), GSK3-phospho SER21/9 (CS9331), Jun-C phospho SER63 (CS9261, SC7980-R), jun-C all forms (CS9262), MAPK/ERK phospho THR202/TYR204 (CS9101), MAPK-ERK all forms (CS9102), MAPK/ERK phospho THR202/TYR204 (CS9106), MAPK-phospho THR202/TYR204 (CS9106), MAPK-phospho THR183/TYR185 (M8159, Sigma Chemical Co., St Louis, MO, USA), MAPK phospho (UBI 06-64206, Upstate Biotechnology Inc, Lake Placid, NY, USA), MAPK5/ERK5 all forms (SC1284, SC1285), ERK5 phospho Thr215 Tyr220 (CS3371), MEK1 all forms (SC219), MEK1 all forms (SC436), MEK1,2 all forms (CS9122), MEK1,2 phospho SER217/SER221 (CS9121), MEK5 all forms (SC10795), MEK5 all forms (SC9320), MSK-1 phospho SER360 (CS9594), MycB phospho SER68 (SC16303R), myc C all forms rabbit (SC788), MycC phospho THR58/SER62 (CS9401, SC8000R), p27 (SC528), p27KIP1 all forms (MS-256-P0, clone 16P07 Ab1), p27 phospho SER10 (SC12939R), p38MAPK all forms (CS9212), p38MAPK phospho THR180/TYR182 (CS9211), p53 phospho SER15 (SC11764-R), p57 (SC8298), p57KIP2 all forms (MS-1062-P0, Ab6, clone 16P07), 3-phosphoinositide-dependent protein kinase (PDK) phospho SER241 (CS3061), PDK phospho substrate (CS2291, protein kinase (PK) A (PKA) phospho substrate (CS9621), PKC phospho substrate (CS2261), Raf1 all forms (SC7198), retinoblastoma (Rb) protein phospho SER795 (CS9301, SC7986R), ribosomal S6 kinase (RSK) 1 phospho THR573 (RSK1) (CS9346), RSK1 all forms (SC231), RSK1 phospho SER380 (CS9341), 90RSK3 all forms (SC1431), 90RSK2 all forms (SC1430), RSK1 all forms (RSK1) (CS9342), RSK1 phospho THR359/SER363 linker (RSK1) (CS9344), RSK2 all forms (SC1430), RSK3 all forms (SC1431), RSK2,1 phospho SER380 (SC11756), RSK3 phospho (CS9345), stress activated protein kinase (SAPK)/JNK all forms (CS9252), SAPK/JNK phospho THR183/TYR185 (CS9251), SOS1 all forms (SC10803, SC256), STAT1 phospho TYR701 (CS9171), THR phospho (SC9381), TYR phospho (PY350)(SC18182). All antibodies designated CS are from Cell Signaling (Beverly, MA, USA), all antibodies designated SC are from Santa Cruz Biotechnology (Santa Cruz, CA, USA) and all antibodies designated MS are from Lab Vision (Fremont, CA, USA).
Collection of mouse embryos
Standard techniques were used for obtaining mouse embryos (Hogan et al. 2002). Female MF-1 mice (4–5 weeks old, Harlan Sprague Dawley, Indianapolis, IN, USA) were injected intraperitoneally with 10 IU pregnant mares’ serum gonadotropin (Sigma Chemical Co.), followed by an injection of 7.5 IU human chorionic gonadotropin (Sigma Chemical Co.) 44–48 h later. After the second injection, females were housed overnight with C57BL/6J x SJL/J F1 hybrid males (Jackson Laboratories, Bar Harbor, ME, USA). Noon of the day following coitus was considered day E0.5. For immunocytochemical (ICC) analysis, embryos were obtained at the morula/early cavitation blastocyst (E3.5), or at the 8-cell/compaction (E2.5) stage; for reverse transcriptase-polymerase chain reaction (RT-PCR), embryos were collected at the following stages: unfertilized egg, 2-cell stage (E1.5), 8-cell/compaction stage (E2.5) and morula-early blastocyst (E3.5) stage. The animal use protocols were approved by the Wayne State University Animal Investigation Committee.
Placenta cell culture
Mouse TSC (Tanaka et al. 1998) and SV40 large T transformed human trophoblast cells (HTR) (Graham et al. 1993) were cultured as described. In a few experiments, TSC were cultured overnight with 0.5 µg/ml of a commercial colchicine analog, Karyomax Colcemid (Gibco/BRL Gaithersburg, MD, USA), which blocked most cells in late G2-prophase, not in metaphase.
Indirect immunocytochemistry and nuclear staining
For immunocytochemical analysis, TSC, HTR and E3.5 mouse embryos were fixed for 30 min in 2% fresh paraformaldehyde (pH 7.4) in phosphate-buffered saline (PBS), quenched with 0.1 M glycine, and permeabilized for 10 min with 0.25% Triton X-100. The embryos were stained with primary antibodies (diluted at 1:100 in PBS-Tween with 10% fetal calf serum). The primary antibody was followed by staining with biotinylated IgG (Vector Labs, Burlingame, CA, USA). Proteins were visualized with fluorescein isothiocyanate (FITC) coupled to streptavidin (Vector Labs). Nuclear counterstaining was carried out with Hoechst 33258 (10 µg/ml). Photomicrography was carried out with a Leica DM IRE2 epifluorescence microscope with a Retiga 1350 Ex cooled charge coupled device controlled electronically by SimplePCI AI module software. Nearest or no neighbor deconvolution was performed using the SimplePCI DNN module. Photographs were analyzed using Photodex CPIC and C-Imaging Simple PCI intensity analysis software (Compix Inc., Imaging Systems, Cranberry Township, PA, USA) and formatted for presentation using Adobe Photoshop 6.0 (San Jose, CA, USA). All fluorescence photos were handled and analyzed in the same way. All experiments were repeated at least twice with similar results.
Statistical analysis
The data in this study are representative of 2–3 independent studies and are given as means ± S.D. Statistical significance of differences between different samples was calculated by Student’s t-test (SPSS 10.0 and SISA website, Uitenbroek 1997). P-values of less than 0.05 were considered significant.
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Results |
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) in embryos, and in TSC and HTR cells. In general, all threonine substrates are elevated at mitosis (Fig. 2; note that figures including all controls for published Figs 2–8 are provided as supplementary figures to the online version of Reproduction (see http://reproduction-online.org/content/vol128/issue5/index.shtml); supplemental Fig. 6), suggesting that serine-threonine kinase plays a role in the regulation of mitosis. In embryos, TSC and HTR it was found that among the individual serine-threonine and tyrosine kinases studied, the following had a high level of phosphorylation during mitosis: ATM (ataxia telangiectasia mutants, note that 5 additional figures not published are available at an on-line database; supplemental Fig. 1), MEK1, 2 and p27 (Fig. 3, supplemental Fig. 7), RSK1, 3 (Figs 4 and 5, supplemental Figs 8 and 9), and p38MAPK (Fig. 6, supplemental Fig. 10) (Table 1). Among the transcription factors, we found a high mitotic phosphorylation of MycB (supplemental Fig. 2), MycC (Fig. 7, supplemental Fig. 11), and Cdx (Fig. 8, supplemental Fig. 12), in embryos, HTR, and TSC (3/8 phosphoprotein transcription factors studied had elevated M phase fluorescence) (Table 2).
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and 2. The duration of their elevation during mitosis is shown in Fig. 9. Mitosis typically lasts for approximately one hour in somatic cells, and only a few of the proteins studied had elevated phosphorylation during all of mitosis. The cell cycles in both HTR and TSC cells are close to 24 h (data not shown) and the preimplantation mouse embryo has a cell cycle at E3.5 of about 12 h (Pedersen 1987, Hogan et al. 2002). Confidence in our ability to detect low frequency events such as meta-phase, or other segments of the M phase, was based on a survey of over 60 000 micrographs of embryos and placental cell lines. The morphology of mitotic cells was clear in HTR and TSC. In embryos, it was more difficult to detect classic metaphase plates although they were visible(RSK1, Wang et al. 2004). However, the elevation in fluorescence intensity in a fraction of the cells in embryos occurred only for those antibodies that also showed an elevation of fluorescence intensity in obviously mitotic HTR and TSC. In addition, the fraction of nuclei of TSC, HTR, or embryos that had an elevated fluorescence intensity was in the range of 1–4% (data not shown), corresponding to the predicted fraction of unperturbed cells that would be in M phase (or some segment of M-phase) for 1 h or less/24 h cell cycle.
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; p53 phospho SER15, supplemental Fig. 3) or the fluorescence was elevated during cell cycle phases besides the M phase (Table 2; p57, Ets2, supplemental Figs 4 and 5 respectively). This is in agreement with previous studies that showed that p53 phospho SER15 is highest in cyclic somatic cells in early G1 phase (Buschmann et al. 2000), and that p57 is activated during endocycle S phase and during the terminal G1 phase of mitotic trophoblasts (Zhang et al. 1998, Hattori et al. 2000).
The location of phosphoproteins elevated during mitosis is tabulated in Table 3. The majority of phosphoproteins were detected in the spindle complex, but p38MAPK phospho was detected in the spindle pole, and Cdx2 was localized with the DNA. This suggests, since many of the phosphoproteins are in the MAPK pathway, that MAPK may be involved with the regulation of the embryonic spindle complex, consistent with a role for MEK-MAPK in mitosis in Swiss 3T3 cells (Willard & Crouch 2001). Note that the implied mitotic function of a given phosphoprotein may change quickly over developmental time, as we could find no elevated MAPK phospho during mitosis in preimplantation embryos using four anti-MAPK phospho antibodies, although this has been reported in post-implantation embryos (Corson et al. 2003). Although the great majority of this study was undertaken in reviewing large numbers of micrographs of unperturbed cultured placental cells and embryos, we did perform one study with a commercial colcemid analog, Karyomax. We found that, as in some other cell types (manufacturer’s notes), overnight incubation of TSC with Karyomax elevated the fraction of cells with condensed, smaller, circular nuclei that were putative late G2/prophase. Normally, MEK1, 2 phospho was elevated and detected in cells in metaphase or anaphase where it appeared to be in the spindle complex, or in a very small fraction of cells with condensed nuclei where phosphoprotein was detected as spots on the DNA (Fig. 3A, B, C, supplemental Fig. 7). The Karyomax protocol also elevated the fraction of cells with elevated fluorescence for MEK1, 2 phospho (Fig. 3G, H, I, supplemental Fig. 7) and p27 phospho (Fig. 3J, K, L, supplemental Fig. 7). Interestingly, this treatment also created similar 1-, 2-, and 4-spotted circular nuclei that were correlated with TSC sheet dispersion and nuclear size increase, suggesting that the differentiation state of trophoblast cells might correlate with MEK1, 2 and p27 expression around M phase. This brief study produced the desired result of increasing the fraction of cells with elevated phosphoprotein expression at or around M phase. However, the lack of metaphase block in this cell type, and the inability to associate localization of nuclear spots with function in unperturbed cells, led us to discontinue this avenue of M phase testing. It is interesting to note that (1) possible co-localization of p27 and MEK1, 2 might suggest an enzyme substrate interaction, and (2) at a very low frequency MEK1, 2 nuclear spots were seen in unperturbed TSC. Point number (2) suggests that the localization in the DNA may not be an artifact of tubulin depolymerization caused by Karyomax, but may reflect a low frequency event in unperturbed cells. This suggests that the proper colchicine derivative might be used in studies of M phase function of phosphoproteins in TSC and embryos.
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). All phosphoproteins had a higher intensity at M phase than in interphase cells, in the range of 1.5–5.6 (mean = 2.8) for ratios of raw quantitated immunofluorescence to 2.0–6.2 (mean = 3.8) for the same ratios after a no-antibody background was subtracted from both the means for the M phase (numerator) and interphase (denominator). In baseline studies for each antibody, it was shown that the fluorescence for each antibody was hgiher than with no-antibody, non-immune serum, or for antibody with co-addition of excess immunizing antigen (data not shown). One weakness of the study is that the pictures were taken by different individuals and they had a tendency to shoot micrographs on the high or low intensity range of the 0–255 units/pixel intensity range of the Simple PCI software. The micrographs were taken to emphasize the differences between interphase and M-phase fluorescence. In baseline studies for each antibody, it was shown that the fluorescence for each antibody was higher than with no-antibody, non-immune serum, or for antibody with co-addition of excess immunizing antigen (data not shown). The high end of the fluorescence range is not linear due to pixel saturation and so the ratios may be an underestimate of the intensity of M-phase fluorescence and the corresponding fractions of protein populations that are phosphorylated.
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Discussion |
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Mitosis requires a large reorganization of the cellular cytoskeleton. Microtubules are reorganized to form a bipolar spindle; the chromosomes become condensed, attach to the spindles at their kinetochores and are segregated into two daughter cells. Reorganization of the mitotic cytoskeleton requires a large, rapid surge of serine-threonine protein phosphorylation, controlling signaling events that coordinate mitotic processes. Our data (Fig. 2) are consistent with the increase in all threonine phosphorylation substrates at M phase. An important trigger of the phosphorylation surge is the cyclin-dependent kinase (CDK), Cdc2. After CDK is activated, mitotic serine/threonine kinases in three families - the polo kinases, aurora kinases and the NIMA-related kinases (Nrk) - govern mitosis (Piwnica-Worms 1996, O’Connell et al. 2003). These mitosis-specific enzymes may also control enzymes recruited from other pathways that function during interphase. For example, phosphatidylinositol-3 kinase (PI3Kinase), 3-phosphoinositide-dependent protein kinase (PDK), Akt1 (Dangi et al. 2003), CDK2 (Doree & Galas 1994), MycC (Niklinski et al. 2000), Raf1, MEK1, 2, MAPK1, 2 and RSK1, 2, 3 (Willard & Crouch 2001) are involved with M phase in somatic cells, and in G1-S phase signaling (Sears et al. 2000, Wilkinson & Millar 2000, Rappolee 2003). The entire MAPK pathway is detected in preimplantation mouse embryos (Wang et al. 2004, Xie et al. 2004). Little work has been done on the interaction of the MAPK pathway with the three mitosis-specific enzyme families during mitosis. But, during meiosis, MAPK can be upstream of polo-like kinase in starfish oocytes (Okano-Uchida et al. 2003), MAPK can regulate NIMA-related kinases in mouse spermatogenesis (Di Agostino et al. 2002), but MAPK pathway is apparently independent of aurora kinases in frog oocytes (Maton et al. 2003). This is the first report of high levels of expression for these MAPK pathway phosphoproteins in late preimplantation embryos and placental cells at M phase. These data are consistent with a putative M phase function of MAPK pathway enzymes in early placental lineage cells.
It is important to keep these findings in mind when planning experiments and interpreting data regarding G1-S phase decision making in the early embryo. If measuring induction of interphase responses to growth factors by kinases or transcription factors using quantitative immunofluorescence, elevated fluorescence in mitotic cells (‘mitotic hotspots’) should be avoided. Alternatively, attempts can be made to synchronize cell divisions in order to avoid M phase. Similarly, if loss-of-function perturbations are performed, investigators should be alert for M phase phenotypes. An additional consideration is that alternative functions of the enzyme or transcription factor besides those controlling G1-S phase progression may also occur during G1-S phase.
The mitotic function of kinases changes during development. It is suggested, for example, that MEK1, 2 function is required for M phase completion as the MEK1, 2, 5 inhibitor, U0126, can block mitosis (Willard & Crouch 2001). Therefore, MEK seems to be a dominant G1-S phase kinase used at M phase, but MAPK seems not to be as important in somatic cells (Harding et al. 2003) or in mouse embryos during M phase of the first two cleavage divisions (Iwamori et al. 2000). Our data are in agreement with these reports. Like the 1- to 4-cell stage embryo (Iwamori et al. 2000), MEK1, 2 participates in M phase later in preimplantation development as shown by immunocytochemical means. In contrast to the 1- to 4-cell stage embryos, Raf1 is not highly phosphorylated during M phase in later stage preimplantation embryos or in TSC and HTR. Dissimilar to our data and that of Iwamori and colleagues, MAPK phospho is elevated in post-implantation embryos at M phase (Corson et al. 2003). It seems that the embryo may use different sets of kinases at M phase during different phases of development. Therefore, an additional caution may be that the data presented here may apply to preimplantation development, but each researcher may have to re-examine the expression of these kinases and transcription factors during each period of embryonic development studied.
This study was based upon a large scan of proteins and phosphoproteins using 153 antibodies and 49 phospho-specific antibodies in ‘unperturbed’ embryos ex vivo, and placental TSC and HTR cultured under normal proliferation-promoting conditions. Approximately, 60 000 fluorescence micrographs were recorded, allowing low frequency, short-duration events such as metaphase or anaphase a good opportunity to be observed. Since the preimplantation embryo is translucent and small (having less than 100 cells through E3.5), it lends itself to immunocytochemistry more than to Western blot analysis. In this study, we focused on a mini-proteomics approach where immunocytochemistry was performed in embryos and cell lines. In other studies (Wang et al. 2004, Xie et al. 2004, data not shown), Western blots were analyzed for TSC and HTR, cell lines that represent about 75% of cells in the E3.5 embryo, and the antibodies tested in TSC or embryos are indicated in Tables 1 and 2. A weakness of this study is that Western blots were not performed in the embryos themselves. Such a study would be very prohibitive in cost. A strength of this study is that 29 of the proteins reported here had at least two antibodies that yielded similar results, and that all phosphoproteins, except p53, had similar frequencies of cells with elevated phosphoprotein fluorescence in TSC/HTR as in embryos. In the case of p53, elevated p53 occurred during obvious M phase and also during other apparent cell cycle phases. This made these results difficult to interpret as HTR is transgenic for SV40 large T antigens and this transforming may affect p53 stability and the dynamics of phosphorylation (Graham et al. 1993, Meek 2002). In addition, TSC may partially represent a period of placental lineage development slightly after preimplantation development. All the antibodies with no elevated phosphoprotein fluorescence in TSC/HTR also had no elevated phosphoprotein fluor-escence in embryos. The congruence of negative and positive findings for elevation of phosphoproteins at M phase was complete for TSC/HTR compared with embryos except for one phosphoprotein.
Several proteins had a unique M phase localization. Cdx2 is, like aurora-B kinase, a cell cycle M-phase passenger (Higuchi & Uhlmann 2003) that moves from centromeres to the spindle midzone during mitosis, functioning throughout mitosis in chromosome condensation and segregation (Adams et al. 2001).
p38MAPK was detected in the spindle poles. p38MAPK is detected throughout preimplantation mouse development (Zhong et al. 2004), and mediates mitosis during early Xenopus cleavage divisions and is located in the spindle pole (Takenaka et al. 1998). The majority of phosphoproteins were observed in the putative spindle complex.
In summary, this study shows that a little under half of the signaling enzymes and transcription factors studied had elevated levels of phosphorylation at M phase in preimplantation mouse embryos and placental cell lines, suggesting that caution must be used in interpreting expression studies and cause-and-effect experiments aimed at testing the role of these phosphoproteins during G1 to S phase decision making. The results also suggest that the studies primarily aimed at testing the role of these phosphoproteins in early embryo/placental M phase function would also be of interest.
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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 Y. Xie, W. Zhong, Y. Wang, A. Trostinskaia, F. Wang, E.E. Puscheck, and D.A. Rappolee Using hyperosmolar stress to measure biologic and stress-activated protein kinase responses in preimplantation embryos Mol. Hum. Reprod., July 1, 2007; 13(7): 473 - 481. [Abstract] [Full Text] [PDF]
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