Association of cdk2 kinase with the transcription factor E2F during S phase

Science ◽  
1992 ◽  
Vol 255 (5048) ◽  
pp. 1144-1147 ◽  
Author(s):  
M Pagano ◽  
G Draetta ◽  
P Jansen-Durr
Keyword(s):  
Transcription Factor ◽  
S Phase ◽  
Transcription Factor E2f

scholarly journals Blocking the transcription factor E2F/DP by dominant-negative mutants in a normal breast epithelial cell line efficiently inhibits apoptosis and induces tumor growth in SCID mice.

1996 ◽  
Vol 183 (3) ◽  
pp. 1205-1213 ◽  
Author(s):  
R C Bargou ◽  
C Wagener ◽  
K Bommert ◽  
W Arnold ◽  
P T Daniel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Dominant Negative ◽  
Serum Starvation ◽  
Cycle Progression ◽  
Transcription Factor E2f

The transcription factor E2F is regulated during the cell cycle through interactions with the product of the retinoblastoma susceptibility gene and related proteins. It is thought that E2F-mediated gene regulation at the G1/S boundary and during S phase may be one of the rate-limiting steps in cell proliferation. It was reported that in vivo overexpression of E2F-1 in fibroblasts induces S phase entry and leads to apoptosis. This observation suggests that E2F plays a role in both cell cycle regulation and apoptosis. To further understand the role of E2F in cell cycle progression, cell death, and tumor development, we have blocked endogenous E2F activity in HBL-100 cells, derived from nonmalignant human breast epithelium, using dominant-negative mutants under the control of a tetracycline-dependent expression system. We have shown here that induction of dominant-negative mutants led to strong downregulation of transiently transfected E2F-dependent chloramphenicol acetyl transferase reporter constructs and of endogenous c-myc, which has been described as a target gene of the transcription factor E2F/DP. In addition, we have shown that blocking of E2F could efficiently protect from apoptosis induced by serum starvation within a period of 10 d, whereas control cells started to die after 24 h. Surprisingly, blocking of E2F did not alter the rate of proliferation or of DNA synthesis of these cells; this finding indicates that cell-cycle progression could be driven in an E2F-independent manner. In addition, we have been able to show that blocking of endogenous E2F in HBL-100 cells led to rapid induction of tumor growth in severe combined immunodeficiency mice. No tumor growth could be observed in mice that received mock-transfected clones or tetracycline to block expression of the E2F mutant constructs in vivo. Thus, it appears that E2F has a potential tumor-suppressive function under certain circumstances. Furthermore, we provide evidence that dysregulation of apoptosis may be an important step in tumorigenesis.

scholarly journals The transcription factor E2F-1 is a downstream target of RB action.

1995 ◽  
Vol 15 (2) ◽  
pp. 742-755 ◽  
Author(s):  
X Q Qin ◽  
D M Livingston ◽  
M Ewen ◽  
W R Sellers ◽  
Z Arany ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Repression ◽  
Mutational Analysis ◽  
S Phase ◽  
G1 Arrest ◽  
Transactivation Domain ◽  
Downstream Target ◽  
Transcription Factor E2f ◽  
Phase Entry

Reintroduction of RB into SAOS2 (RB-/-) cells causes a G1 arrest and characteristic cellular swelling. Coexpression of the cellular transcription factor E2F-1 could overcome these effects. The ability of E2F-1 to bind to RB was neither necessary nor sufficient for this effect, and S-phase entry was not accompanied by RB hyperphosphorylation under these conditions. Furthermore, E2F-1 could overcome the actions of a nonphosphorylatable but otherwise intact RB mutant. These data, together with the fact that RB binds to E2F-1 in vivo, suggest that E2F-1 is a downstream target of RB action. Mutational analysis showed that the ability of E2F-1 to bind to DNA was necessary and sufficient to block the formation of large cells by RB, whereas the ability to induce S-phase entry required a functional transactivation domain as well. Thus, the induction of a G1 arrest and the formation of large cells by RB in these cells can be genetically dissociated. Furthermore, the ability of the E2F-1 DNA-binding domain alone to block one manifestation of RB action is consistent with the notion that RB-E2F complexes actively repress transcription upon binding to certain E2F-responsive promoters. In keeping with this view, we show here that coproduction of an E2F1 mutant capable of binding to DNA, yet unable to transactivate, is sufficient to block RB-mediated transcriptional repression.

scholarly journals Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis.

1994 ◽  
Vol 91 (23) ◽  
pp. 10918-10922 ◽  
Author(s):  
X. Q. Qin ◽  
D. M. Livingston ◽  
W. G. Kaelin ◽  
P. D. Adams
Keyword(s):  
Transcription Factor ◽  
S Phase ◽  
Transcription Factor E2f ◽  
Phase Entry

scholarly journals The transcription factor E2F is required for S phase during Drosophila embryogenesis.

1995 ◽  
Vol 9 (12) ◽  
pp. 1445-1455 ◽  
Author(s):  
R J Duronio ◽  
P H O'Farrell ◽  
J E Xie ◽  
A Brook ◽  
N Dyson
Keyword(s):  
Transcription Factor ◽  
S Phase ◽  
Drosophila Embryogenesis ◽  
Transcription Factor E2f

The Transcription Factor E2F-1 in SV40 T Antigen-Induced Cerebellar Purkinje Cell Degeneration

1998 ◽  
Vol 12 (1-2) ◽  
pp. 16-28 ◽  
Author(s):  
Maria C. Athanasiou ◽  
Wael Yunis ◽  
Natalie Coleman ◽  
Robert Ehlenfeldt ◽  
H.Brent Clark ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Purkinje Cell ◽  
T Antigen ◽  
Cerebellar Purkinje Cell ◽  
Sv40 T Antigen ◽  
Cell Degeneration ◽  
Purkinje Cell Degeneration ◽  
Transcription Factor E2f

scholarly journals Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F.

1992 ◽  
Vol 12 (12) ◽  
pp. 5620-5631 ◽  
Author(s):  
B Shan ◽  
X Zhu ◽  
P L Chen ◽  
T Durfee ◽  
Y Yang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mammalian Cells ◽  
Leucine Zipper ◽  
T Antigen ◽  
Transactivation Domain ◽  
Recognition Sequence ◽  
Cellular Genes ◽  
Genes Encoding ◽  
Associated Proteins ◽  
Transcription Factor E2f

The retinoblastoma protein interacts with a number of cellular proteins to form complexes which are probably crucial for its normal physiological function. To identify these proteins, we isolated nine distinct clones by direct screening of cDNA expression libraries using purified RB protein as a probe. One of these clones, Ap12, is expressed predominantly at the G1-S boundary and in the S phase of the cell cycle. The nucleotide sequence of Ap12 has features characteristic of transcription factors. The C-terminal region binds to unphosphorylated RB in regions similar to those to which T antigen binds and contains a transactivation domain. A region containing a potential leucine zipper flanked by basic residues is able to bind an E2F recognition sequence specifically. Expression of Ap12 in mammalian cells significantly enhances E2F-dependent transcriptional activity. These results suggest that Ap12 encodes a protein with properties known to be characteristic of transcription factor E2F.

scholarly journals Functions of Cyclin A1 in the Cell Cycle and Its Interactions with Transcription Factor E2F-1 and the Rb Family of Proteins

1999 ◽  
Vol 19 (3) ◽  
pp. 2400-2407 ◽  
Author(s):  
Rong Yang ◽  
Carsten Müller ◽  
Vong Huynh ◽  
Yuen K. Fung ◽  
Amy S. Yee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Mitotic Cell ◽  
Histone H1 ◽  
Mitotic Cell Cycle ◽  
Osteosarcoma Cell ◽  
Cell Cycle Regulators ◽  
Cyclin A1 ◽  
Transcription Factor E2f

ABSTRACT Human cyclin A1, a newly discovered cyclin, is expressed in testis and is thought to function in the meiotic cell cycle. Here, we show that the expression of human cyclin A1 and cyclin A1-associated kinase activities was regulated during the mitotic cell cycle. In the osteosarcoma cell line MG63, cyclin A1 mRNA and protein were present at very low levels in cells at the G0 phase. They increased during the progression of the cell cycle and reached the highest levels in the S and G2/M phases. Furthermore, the cyclin A1-associated histone H1 kinase activity peaked at the G2/M phase. We report that cyclin A1 could bind to important cell cycle regulators: the Rb family of proteins, the transcription factor E2F-1, and the p21 family of proteins. The in vitro interaction of cyclin A1 with E2F-1 was greatly enhanced when cyclin A1 was complexed with CDK2. Associations of cyclin A1 with Rb and E2F-1 were observed in vivo in several cell lines. When cyclin A1 was coexpressed with CDK2 in sf9 insect cells, the CDK2-cyclin A1 complex had kinase activities for histone H1, E2F-1, and the Rb family of proteins. Our results suggest that the Rb family of proteins and E2F-1 may be important targets for phosphorylation by the cyclin A1-associated kinase. Cyclin A1 may function in the mitotic cell cycle in certain cells.

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