Transcriptional Repressor and Regulation of Cell Cycle Reentry

7 March, 1999

Transcriptional Repressor and Regulation of Cell Cycle Reentry

The E2F family of proteins (E2F-1 to -5) is required to establish the correct cell cycle-dependent transcription of genes that direct the process of cell division (progression from the G1 to the S phase of the cell cycle). They can either repress or activate the transcription of E2F-responsive genes, depending on whether or not they are associated with retinoblastoma susceptibility protein pRB, p107, or p130. The association of E2F-1 with pRB, for example, masks the E2F-1 transactivation domain and actively inhibits promoter elements to repress transcription of responsive genes, resulting in growth inhibition. The growth-inhibiting properties are inactivated by phosphorylation of pRB catalyzed by cycline-dependent kinases (cdks).
The E2F may also act as transcriptional repressor with growth-suppressing activity when comolexed with p107 and p130 that are "pocket proteins." E2F-4 may be converted this way into a transcriptional suppressor by binding to p107, that appears to play a role in G0 entry as shown in human bronchial epithelial and other cells (Lee HY et al, 1998: uid=9486971). When pocket proteins are phosphorylated by cdks, active E2F is released to activate responsive genes such as B-myb, cyclin A, and cyclin E to exit G1 phase into S phase.

The E2F is a heterodimer of an E2F-like and a DP-like subunit (5 E2Fs and DP-1 and DP-2). Conserved E2F domains mediate heterodimerization, DNA binding, picket protein binding, and transactivation, whereas E2F-DP formation is required for high-affinity DNA binding. E2F proteins may be grouped into 2 classes: E2F-1, -2 and -3 that bind preferentially to pRB; E2F-4 and -5 that bind to p107 and p130. E2F family members play distinct roles in cell cycle control. E2F1 may function as a specific signal for the initiation of an apoptosis pathway (DeGregori J et al, 1997: uid=97352783). pRB and p107/p130 also provide differential regulatory functions for the E2F in the expression of target genes (Hurford RK Jr et al, 1997: uid=97336077).

Recently, another E2F family member, EMA, was cloned from mouse (Morkel M et al, 1997: uid=9403682) , and analogous E2F-6 from mouse (Trimarchi JM, et al 1998: uid=98169460) and human (Gaubatz S et al, 1998: uid=98356133). The dimerization and DNA binding properties of EMA/E2F-6 are similar to those of the other E2F family members. However, EMA/E2F-6 lacks of a pocket protein binding and transactivation domain. Thus, it is not regulated by pRB, p107, or p130. It is also unable to activate transcription. Rather, it counteracted other E2F complexes to repress the transcription of E2F responsive genes; namely, EMA/E2F-6 is a transcriptional repressor, and forms a unique third group within the E2F family. E2F-6 is a nuclear protein that can form heterodimers with the DP proteins (both DP-I and DP-2) in vitro and in vivo. The complex formed between E2F-6 and the DP proteins, possesses high DNA binding activity, displaying a preference for a <TTTCCCGC> E2F recognition site (Cartwright P et al, 1998; uid=9704927), which is slightly different to the E2F consensus site derived from the E2 promoter <TTTCGCGC>. In contrast to the other members of the E2F family, ectopic expression of E2F-6 inhibits transcription from promoters possessing E2F recognition sites rather than activating transcription. In addition, overexpression of E2F-6 suppresses the transactivational effects of coexpression of E2F-1 and DP-1. The inhibitory effect of E2F-6 is dependent on its DNA binding activity and its ability to form heterodimers with the DPs. The domain for this repression was found in the carboxyl terminus in human E2F-6, whereas it was in the amino terminus in mouse EMA. E2F-6 did not induce growth arrest but inhibits cell cycle reentry from G0 phase of NIH 3&3 cells under the same experimental conditions (Gaubatz S et al, 1998: uid=98356133). It is conceivable that E2F-6 normally recognizes and represses E2F-dependent target genes that are required for exit from G0 but not for normal cell cycle progression.

The rapid elucidation of regulatory mechanisms of mammalian cell cycle inspired a notion that compounds that inhibit specific factors involved in the cell cycle progression should be good candidates for the development of anticancer agents. Cyclins, kinases and natural inhibitors particularly at G1 phase of the cell cycle have been looked upon as potential targets in such endeavor. This notion arises from the concept that cancer cells deviate from the normal regulation and grow faster than the normal cell; thus, growth-inhibiting compounds might serve as cancer growth inhibitors. The experience in the past efforts reveals that cancer cells do not always grow faster than the normal cell in specific tissues and in fact most anticancer agents developed according to this concept often had debilitating and deleterious side effects and did not make for even minimal prolongation of the patient survival time. When anticancer agents are to be pursued in terms of growth inhibition, it would be better off to look at G0 and perhaps G2/M phases of the cell cycle. Compounds that regulate these phases might keep cell growth in check without aberrant effect on the cell. The G0 phase of the cell cycle is defined but yet obscure. With E2F-6 as a leverage, the inhibition of cell cycle reentry as discussed above might be a potentially useful approach in the development of new kinds of anticancer agents.　

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