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[Cancer Research 64, 1607-1610, March 1, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

Detection of Cyclin B1 Expression in G1-Phase Cancer Cell Lines and Cancer Tissues by Postsorting Western Blot Analysis

Manli Shen1, Yongdong Feng1, Chun Gao1, Deding Tao1, Junbo Hu1, Eddie Reed2, Qingdi Q. Li2 and Jianping Gong1

1 Tongji Cancer Institute and Center for Molecular Medicine, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China, and 2 Mary Babb Randolph Cancer Center and Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine and Robert C. Byrd Health Sciences Center, Morgantown, West Virginia


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Protein complex of cyclin B1 and cyclin-dependent protein kinase 1 induces phosphorylation of key substrates that mediate cell cycle transition during the G2-M phase. It is believed that cyclin B1 accumulates in the S phase of the cell cycle and reaches the maximal level at mitosis but is absent in G1-phase cells. In the present study, we demonstrated that cyclin B1 was expressed in the arrested G1-phase MOLT-4 lymphocyte leukemia cells and in G1 phase T-7 transitional tumor cells, as determined by flow cytometry. In addition, we showed that cyclin B1 was detected in the G1 phase in breast cancer cells from patient tissues and in lymphocytes from patients with leukemia. These findings were confirmed for the first time by postsorting Western blot analysis and by confocal microscopy. Furthermore, by using postsorting Western blotting, we found that cyclin B1 was expressed in different time-window sections of the G1 phase under different conditions. For the asynchronously growing T-7 cells, cyclin B1 was detected in early G1 phase, whereas in MOLT-4 cells arrested in G1-S phase, cyclin B1 was mainly detected in late G1 phase. We propose that the cyclin B1 expressed in the G1 phase may differ from that expressed in the G2-M phase, and that this unscheduled type of cyclin B1 may play an important role in tumorigenesis and apoptosis.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The eukaryotic cell cycle consists of the following four discrete phases: G1, S, G2, and M. Cyclins and the cyclin-dependent protein kinases (CDKs) are two major classes of regulators for cell cycle progression in all eukaryotes (1, 2, 3) . The CDKs are enzymes that phosphorylate other proteins using ATP as the phosphate donor. The role of cyclins is to activate the appropriate CDK at the appropriate time in the cell cycle. Cyclin B1, an important member of cyclin family, is known to form complex with CDK1, which phosphorylates their substrates to urge cells through the G2-M phase (4) . Cyclin B1 has been classified in G2 cyclin because the accumulation of this protein begins at the S phase, essentially restricted to the G2-M transition, reaches the maximal level at mitosis, and then is rapidly degraded at metaphase-anaphase transition (4 , 5) . Although the scheduled expression mode of cyclin B1 has been reported to be strictly conserved from yeast to mammalian, researchers have reported that cyclin B1 can also be detected in the G1 phase under certain circumstances. Pines et al. (6) reported that cyclin B1 mRNA and protein in HeLa cells were actually found to be present in G1-phase cells after a thymidine-aphidicolin block; however, significant levels of cyclin A or cyclin B1 in the G1 phase were not detected by immunofluorescence microscopy (7) . Gong et al. (8 , 9) found that the expression of cyclin B1 could be detected in synchronized cells arrested at the G1 phase, as determined only by flow cytometry. Viallard et al. (10 , 11) also showed that cyclin B1 accumulated at the G1 phase in human leukemic cell lines. However, cyclin B1 expression in asynchronously growing subgroup cells was not studied at that time because of technique limitations. Besides, they were not able to determine the unscheduled mode of cyclin B1 in G1-phase cells or the maximal level of cyclin B1 expression in G1-phase cells.

The current study was undertaken to investigate the unscheduled cyclin B1 expression in different human cancer cells. We have established a new method called postsorting Western blotting for the study of unscheduled cyclin B1 expression in asynchronously growing cells. We have confirmed, by using this new method, that the strictly conservative protein cyclin B1 in the G2-M phase is expressed in unscheduled mode in the G1 phase of the cell cycle. We have also demonstrated that cyclin B1 is expressed in different time-window sections of G1 in the G1-phase human tumor cells.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Isolation of the Cells from the Cancer Tissues of Patients.
We first isolated human breast cancer cells from the breast cancer tissues of patients. For this, 17 fresh breast cancer tissues were placed in RPMI 1640 after being acquired from operation. Fatty, necrotic, and other extraneous tissues were trimmed and minced. The trimmed tissues were filtered through 1-mesh cell sieves and rinsed. Finally, the sieved cells were centrifuged for 10 min at 1000 rpm, and cell pellets were resuspended in 1 ml of culture medium. In addition, lymphocytes were isolated by density gradient centrifugation from the specimens of 15 patients with leukemia. Flow cytometry analysis and cell sorting for the primary human breast cancer cells and lymphocytes were the same as those for the MOLT-4 and the T-7 cell lines, as described below.

Cell Analysis by Flow Cytometry.
Cell culture was performed as described previously (12 , 13) . Cell synchronization (double thymidine block) was performed as described previously (8) , and cell analysis by flow cytometry was also performed as described previously (12) .

Cell Sorting.
Cell sorting was performed by using a FACSVantage (Becton Dickinson, San Jose, CA). G1-phase cells were sorted based on DNA diploidy. To sort subgroups in the G1 phase, the cells were first labeled with cyclin E antibody, and then the labeled cells were sorted in tubes precoated with FCS, containing 0.5 ml of FCS. The sorting windows were selected to include the cells in G0, G1-early, and G1-late phase, respectively, based on the cyclin E expression threshold. Cyclin B1 expression in sorted cell groups was then analyzed by Western blotting and confocal microscopy.

Confocal Fluorescence Microscopy after Sorting.
Cell morphological characters sorted in different time-window sections of the G1 phase were screened using a laser scanning confocal microscope (SPII Confocal System; Leica Microsystems, Inc., Exton, PA).

Postsorting Western Blot Analysis.
Cells collected by pipetting were lysed by Laemmli sample buffer [2% SDS, 62 mM Tris, 10% glycerol, 5% ß-mercaptoethanol, 0.005% bromphenol blue (pH 6.8)]. Samples were boiled for 5 min and then supersonicated. Total cellular proteins from 0.5 x 106 cells/sample in each lane were subjected to electrophoresis in 12% polyacrylamide gel. The proteins in the gel were then transferred to polyvinylidene difluoride membrane in mini Vertical Electrophoresis (VE) systems (Amersham-Pharmacia, Piscataway, NJ). After the transfer, the membrane was saturated for 1 h with 5% nonfat dry milk in Tris-buffered saline (pH 7.6), with 0.1% Tween 20. The blots were then incubated with primary mouse antihuman cyclin B1 antibody (diluted to 1:1000), followed by alkaline phosphatase-conjugated horse antimouse IgG secondary antibody (Vector Laboratory, Inc., Burlingame, CA) diluted to 1:1000, and the results were detected using enzyme reaction. Molecular weights were determined by comparison to known markers.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Detection of Cyclin B1 Expression in G1-Phase Cancer Cells Arrested in G1-S Phase.
We first determined whether cyclin B1 could be detected in the G1 phase of U-937, T-7-transformed cells, and MOLT-4 leukemic cells blocked in G1-S phase. Fig. 1Citation compares the bivariate cyclin B1 versus DNA-content distribution of MOLT-4 cells with that of the arrested MOLT-4 cells and transformed T-7 cells. Scheduled expression of cyclin B1, believed to be positive strictly in G2-M-phase cells, was observed in exponentially growing MOLT-4 cells. In contrast, cyclin B1 in the G1-phase MOLT-4 cells was negative (Fig. 1A)Citation . However, analysis of cyclin B1 expression in MOLT-4 cells blocked in G1-S phase and in T-7-transformed cells revealed that G1-phase cells had cyclin B1-positive fluorescence signals (Fig. 1, C and D)Citation . These dot plots indicate that cyclin B1 is expressed in cells residing not only in the G2-M phase but also in the G1 phase of the cell cycle.



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  		Fig. 1. Bivariate distributions of cell populations from untreated and arrested MOLT-4 cells and from T-7 cells. MOLT-4 cell blots incubated with the isotypic IgG instead of cyclin B1 antibody were used as a nonspecific antibody (IgG) control (A). Untreated MOLT-4 cells were found to have the scheduled expression of cyclin B1 in populations of G2-M cells but not in G1-S-phase cells (B). In contrast, T-7 cells were shown to be cyclin B1-positive in G1-phase cells (C), and MOLT-4 cells arrested at the G1 phase had the same unscheduled cyclin B1 expression pattern of T-7 cells (D).

 
Cyclin B1 Expression in G1 Phase Cancer Cells Was Confirmed by Confocal Microscopy.
Next, we confirmed that cyclin B1 expression occurred in G1-phase cells by confocal microscopy (Fig. 2)Citation . The cells sorted in exponentially growing G1-phase MOLT-4 cells were used as negative controls (Fig. 2A)Citation . As can be observed, the fluorescence of cyclin B1 in the G1-phase cells is located in the nuclei of both the T-7 cells (Fig. 2B)Citation and the MOLT-4 cells (Fig. 2C)Citation .



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  		Fig. 2. Confirmation of cyclin B1 expression in G1-phase cells by confocal microscopy. We confirmed that cyclin B1 could be detected in G1-phase cells by confocal microscopy. A, the negative control of cyclin B1 expression. B, cyclin B1 expressed in the G1-early phase of transformed T-7 cells. C, cyclin B1 expression occurred in the G1-late phase of blocked MOLT-4 cells. As can be observed, the fluorescence of cyclin B1 is located in both nuclei of the two G1-phase cells (B and C).

 
The Time-Window Sections of G1 When Cyclin B1 Is Differentially Expressed in Synchronized and Asynchronously Growing Tumor Cells.
Because the level of cyclin E is consecutively increased during G1 phase, we used the fluorescence intensity of cyclin E as a marker for different time-window sections of cells in the G1 phase detected by flow cytometry. All G1-phase populations were divided into the following three groups: G0, G1-early, and G1-late-phase cells, based on the expression of cyclin E detected by immunofluorescence (Fig. 3, A and C)Citation . Western blot analysis of the three sorted subgroups of the G1-phase cells showed that cyclin B1 expression was in G1-early phase in asynchronously growing T-7 cells (Fig. 3B)Citation . In contrast, cyclin B1 expression was mainly in G1-late phase in synchronized MOLT-4 cells (Fig. 3D)Citation .



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  		Fig. 3. Detection of cyclin B1 expression in G1-phase cells by postsorting Western blot analysis. A and C, cyclin E expression in T-7 cells and arrested MOLT-4 cells, respectively. The dot plots indicate that cyclin E expression intensity increases gradually in the G1 phase and peaks at the time when cells enter the S phase. The three windows created based on the fluorescence intensity of this protein represent G0, G1-early, and G1-late sub-phase cells, respectively. B and D, Western blot analysis of cyclin B1 expression in sorted three sub-phases of G1-untreated T-7 cells and blocked MOLT-4 cells. As seen, cyclin B1 can be measured in the G1-early phase of the asynchronously growing T-7 cells (B) and in the G1-late phase of the synchronized MOLT-4 cells (D).

 
Detection of Cyclin B1 Expression in G1-Phase Cancer Cells from the Cancer Tissues of Patients.
Unscheduled expression of cyclin B1 was also found in human primary cancer cells isolated from patient cancer tissues, as described above. Fig. 4ACitation is the contour map plot showing that cyclin B1 was expressed in the G1-phase breast cancer cells derived from patient breast cancer tissues. Similarly, Fig. 4BCitation shows that cyclin B1 expression was also detected in the G1-phase lymphocytes derived from the patients with leukemia. Fig. 4DCitation is a representative result of the Western blot analysis of the sorted G1-phase breast cancer cells. As seen, cyclin B1 was expressed in both whole cells and the sorted G1-phase cells, suggesting that these in vivo uncontrolled proliferating tumor cells exhibited expression of cyclin B1 not only in the G2-M phase but also in the G1 phase of the cell cycle.



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  		Fig. 4. Cyclin B1 expression in G1-phase cancer cells from cancer tissues of patients. Human primary breast cancer cells from clinical breast cancer tissues (A) and lymphocytes from the patients with leukemia (B) allowed for the observation of unscheduled expression of cyclin B1 occurring in the G1 phase in these cells. C, the sorting window from a DNA histogram of leukemia cells. D, cyclin B1 was expressed in the sorted G1-phase lymphocytes of leukemia patients, as determined by Western blot analysis.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
It is generally believed that scheduled cyclin B1 is expressed in eukaryotic cells, i.e., synthesized first at late S phase, peaked at G2-M phase, and then rapidly degraded by ubiquitin-dependent proteolysis, which was taken for granted to be conservative from yeast to mammalian (1, 2, 3) . However, in recent years some studies have shown that cyclin B1 could be detected in some G1-phase tumor cell lines (10, 11 , 14) . Gong et al. (12) studied the expression of cyclin B1 in MOLT-4 lymphocyte leukemia cells synchronized in the G1 phase of the cell cycle and found unscheduled expression of cyclin B1 in the G1 phase in this cancer cell line, as determined by the bivariate analysis (cyclin versus DNA content) of multiparameter flow cytometry. That method allows one to assay the ectopic expression of cell cycle phase-specific protein (12) . Because the DNA content was used to divide the different time-window sections of cells in the cell cycle, the cells in the G1 phase with the same DNA content could not be divided into any sub-phases. Recently, we noticed that cyclin E is expressed in G1-phase cells continuously and reaches peak level over a threshold at the time of entering into the S phase. Therefore, we selected the fluorescence intensity of cyclin E to be the marker (Fig. 3, A and C)Citation as partition of early and late G1-phase cells (13) . The expression of cyclin B1 in sorted cells can be assayed by a Western blot analysis. This method, which we call postsorting Western blotting, provides an approach to study more precisely the specific protein(s) for the cell cycles in subpopulations of asynchronously growing cells.

Unscheduled cyclin B1 expression in the G1 phase also occurs in primary cancer cells from clinical tumor tissues. Besides leukemia and breast cancer cells examined in the present study, we have shown that unscheduled cyclin B1 was expressed in the G1 phase in other human cancer cells from tumor tissues of patients, including gastric carcinoma, colon cancer, nasopharyngeal carcinoma, and ovarian cancer (data not shown). However, the significance of unscheduled cyclin B1 expression in cancer biology is not clearly defined. Earlier studies reported that the overexpression of cyclins in human tumors was associated with tumor transformation and poor prognosis (15 , 16) . Because cyclin B1 normally forms a heterodimeric complex with CDK1 during the G2 phase resulting in histone kinase activity, which is necessary for the initiation of mitosis, continuous expression of cyclin B1 in tumor cells may allow cyclin B1-CDK1 complex to phosphorylate a series of substrates regardless of the phase in the cell cycle and lead to out of control cell cycle progression. Therefore, the ectopic expression of cyclin B1 in the G1 phase may be one of the mechanisms of carcinogenesis for some cancer types.

The mechanism accounting for unscheduled expression of cyclin B1 in certain tumor cells is not understood at this time. However, there may exist two possibilities, as follows: (a) the synthesis of cyclin B1 in these cells is not limited to the strict period in the cell cycle, and (b) the proteolytic degradation of this protein is impaired. Therefore, low levels of cyclin B1 can be detected during the G1 phase of the cell cycle in some tumor cell lines. No matter what reason may lead to the unscheduled expression of cyclin B1, the presence of cyclin B1 in G1-phase cells may suggest a possible dysfunction or misregulation of the machinery for cell cycle progression.

The localization of ectopic cyclin B1 expression in G1-phase cells is unknown. We show in this report that the restriction period in which cyclin B1 can be detected in the G1 phase is different under different culture conditions. The ectopic cyclin B1 was expressed in early G1 phase in asynchronously growing transformed T-7 cells (Fig. 3, A and B)Citation , whereas in arrested MOLT-4 cells synchronized in the G1 phase by double thymidine blocking, the ectopic cyclin B1 was mainly detected in late G1 phase of the cells (Fig. 3D)Citation . Although endogenous cyclin B1 protein has been considered to be one component of M phase-promoting factor, which urges cells through division, the role of ectopic cyclin B1 in the G1 phase in biological and pathological processes is unclear. We observed recently that when the time for the second thymidine block was increased from 12 to 24 h (or even longer), quite a number of the arrested MOLT-4 cells underwent apoptotic cell death after releasing from block (data not shown), suggesting that this kind of unscheduled cyclin B1, together with CDK1, might be involved in apoptosis under specific circumstances. This hypothesis is supported by some reports showing that the activation of CDK1 was required for apoptosis (17 , 18) . Therefore, based on our observations and those of others, we propose that continuous and sustained expression cyclin B1 in the G1 phase may drive cell cycle progression and lead to uncontrolled cell proliferation, whereas a transient expression of cyclin B1 in the G1 phase may lead to activation of the apoptosis pathways that cause cell death.

In summary, we showed in this study that cyclin B1 was expressed in the G1 phase in the synchronized MOLT-4 cells and asynchronously growing T-7 cells, as accessed by flow cytometry. Additionally, cyclin B1 was detected in the G1 phase in the breast cancer cells from patient tissues and in lymphocytes from the patients with leukemia. Finally, we established a postsorting Western blot technique, and by using this new technique, we demonstrated that cyclin B1 was expressed in early G1 phase in asynchronously growing T-7 cells and in late G1 phase in synchronized MOLT-4 cells. Although the role and importance of G1-phase cyclin B1 in the tumorigenesis and apoptosis of human malignancy are becoming increasingly apparent, the precise mechanisms of unscheduled expression of cyclin B1 have not been completely understood. Studies are in progress to further investigate the different patterns of unscheduled cyclin B1 expression in different tumor cells and to elucidate the role and mechanism of this protein in cell proliferation and cell death.


   FOOTNOTES
 
Grant support: Made possible by funds from the China State Key Basic Research Program (G1998051212), the National Natural Science Foundation of China (Nos. 39670265, 39730270, and 37725027), and the Science Foundation of Ministry of Health (P7070239), and by an NIH/National Center for Research Resources grant (No. P20RR16440-010003).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M. Shen and Y. Feng contributed equally to this work.

Requests for reprints: Jianping Gong, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China. E-mail: jpgong{at}tjh.tjmu.edu.cn or Qingdi Q. Li, MBR Cancer Center, West Virginia University School of Medicine and Health Sciences Center, P.O. Box 9300, Morgantown, WV 26506. Phone: (304) 293-6870; Fax: (304) 293-4667; E-mail: qli{at}hsc.wvu.edu

Received 10/22/03. Revised 1/ 9/04. Accepted 1/15/04.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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