Cyclin A and the retinoblastoma gene product complex with a common transcription factor

Abstract

The retinoblastoma gene (Rb) product is a negative regulator of cellular proliferation, an effect that could be mediated in part at the transcriptional level through its ability to complex with the sequence-specific transcription factor DRTF1. This interaction is modulated by adenovirus E1a, which sequesters the Rb protein and several other cellular proteins, including cyclin A, a molecule that undergoes cyclical accumulation and destruction during each cell cycle and which is required for cell cycle progression. Cyclin A, which also complexes with DRTF1, facilitates the efficient assembly of the Rb protein into the complex. This suggests a role for cyclin A in regulating transcription and defines a transcription factor through which molecules that regulate the cell cycle in a negative fashion, such as Rb, and in a positive fashion, such as cyclin A, interact. Mutant loss-of-function Rb alleles, which occur in a variety of tumour cells, also fail to complex with E1a and large T antigen. Here we report on a naturally occurring loss-of-function Rb allele encoding a protein that fails to complex with DRTF1. This might explain how mutation in the Rb gene prevents negative growth control.

Human papillomavirus type 16 in head and neck carcinogenesis

“…Interestingly, the carboxy terminus of E7 contains a similar zinc-binding domain as the E6. The E7 binds to retinoblastoma protein (pRB) and the related pocket proteins p107 and p130, results in releasing the transcription factor E2F from pRB complexes, and consequently activating genes regulating cell proliferation (Dyson et al 1989;Bagchi et al 1990;Bandara et al 1991). Besides the pRb, the E7 also interacts with various proteins (Table 1), most of which are important regulators of cell growth, expecially the transition of a cell from the G1 to the S-phase of mitosis.…”

Deregulated expression of cell-cycle proteins during premalignant progression in SENCAR mouse skin

“…The p107 and p130 protein levels decreased somewhat at 20 and 30 weeks of promotion, the decrease in p130 being more notable ( Figure 5). E2F transcription factors have been implicated as critical targets for the tumor suppressor pRb and pRbrelated proteins (Bagchi et al, 1991;Bandara et al, 1991;Chellappan et al, 1991). Five members of the E2F family have been described (E2F-1 to E2F-5) but only E2F-1 has been associated with tumorigenesis (Johnson et al, 1994;Singh et al, 1994;Yamasaki et al, 1996).…”

“…Loss of Rb function contributes to the loss of cell growth control in various tumors (Weinberg, 1991). There is considerable evidence that the E2F transcription factors are a critical target for pRb and pRb-related proteins (Bagchi et al, 1991;Bandara et al, 1991;Chellappan et al, 1991). The interaction of pRb with E2F correlates with the capacity of pRb to arrest cell growth in G1 phase (Hiebert, 1993;Hiebert et al, 1992;Qian et al, 1992;Qin et al, 1992).…”

Inhibition of E6 induced degradation of p53 is not sufficient for stabilization of p53 protein in cervical tumour derived cell lines

“…Both oncoproteins exert their transforming activity through interactions with key components of the cellular regulatory machinery. E7 binds to the cellular tumour suppressor pRb and the related pocket proteins (Dyson et al, 1989;Davies et al, 1993), resulting in a release of free E2F and stimulation of proliferation related genes (Bandara et al, 1991;Phelps et al, 1991). The viral E6 protein's principal target is the cellular tumour suppressor p53 ; as a consequence of this interaction, p53 is labelled for ubiquitin mediated degradation, leading to an inhibition of p53's growth regulatory functions (Sche ner et al, 1990;Huibregtse et al, 1991Huibregtse et al, , 1993Crook et al, 1991;Pim et al, 1994).…”