Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein.

Abstract

The cellular protein p107 shares many structural and biochemical features with the retinoblastoma gene product, pRB. We have isolated a full-length cDNA for human p107 and have used this clone to study the function of p107. We show that, like pRB, p107 is a potent inhibitor of E2F-mediated trans-activation, and overexpression of p107 can inhibit proliferation in certain cell types, arresting sensitive cells in G1. Several experiments, however, showed that growth inhibition by pRB and p107 did not occur through the same mechanism. First, in the cervical carcinoma cell line C33A, p107 was able to block cell proliferation, whereas pRB could not, even though both proteins were potent inhibitors of E2F-mediated transcription in this cell line. Second, growth arrest by pRB and p107 was rescued differentially by various cell cycle regulators. Third, some mutants of p107 that cannot associate with adenovirus E1A were still able to inhibit cell proliferation, whereas analogous mutants in pRB are known to be unable to block cell growth. Together, these results suggest a biological role of p107 that is related, but not identical, to that of pRB.

Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins

“…RB is the founder of the RB family of genes and proteins, since two other factors structurally and functionally related, namely p107 (RBL1) (Ewen et al, 1991;Zhu et al, 1993) and Rb2/p130 (RBL2) (Hannon et al, 1993;Li et al, 1993;Mayol et al, 1993), have been subsequently identified. The RB family proteins share a considerable structural homology, primarily at the level of the 'pocket' domain, a complex structure subdivided in A-domain, spacer and B-domain.…”

“…The RB family proteins share a considerable structural homology, primarily at the level of the 'pocket' domain, a complex structure subdivided in A-domain, spacer and B-domain. A-and B-domains are the most conserved among the three RB proteins and are involved in common functional characteristics (Paggi et al, 1996;Mulligan and Jacks, 1998), the most relevant one being the ability to control the cell cycle by negative modulation of the transition between the G1 and S phases (Goodrich et al, 1991;Zhu et al, 1993;Claudio et al, 1994;Starostik et al, 1996). To perform this task, these 'pocket proteins' utilize mechanisms mostly related to inactivation of transcription factors (Kouzarides, 1995), such as those of the E2F family (Cao et al, 1992;Helin et al, 1992Helin et al, , 1993Shirodkar et al, 1992;Beijersbergen et al, 1994;Hijmans et al, 1995;Sardet et al, 1995;Hurford et al, 1997), that promote the cell entrance into the S phase (Ewen, 1994;Weinberg, 1995;Paggi et al, 1996;Mulligan and Jacks, 1998).…”

“…The subsequent characterization of these proteins first identified p105 as the product of the RB gene (Whyte et al, 1988), and then p60 as cyclin A (Giordano et al, 1989;Pines and Hunter, 1990). Later, genes encoding p107 (Ewen et al, 1991;Zhu et al, 1993) and pRb2/p130 (Hannon et al, 1993;Li et al, 1993;Mayol et al, 1993) were cloned using different strategies. Finally p300, together with CBP, defines a family of transcriptional adaptor proteins that are specifically targeted by the E1A oncoprotein (Arany et al, 1995).…”

“…Also, the other two members of the retinoblastoma family, p107 and pRb2/ p130, were first discovered through their association to E1A Herrmann et al, 1991). Later, they were cloned and identified as pocket proteins (Ewen et al, 1991;Hannon et al, 1993;Li et al, 1993;Mayol et al, 1993;Zhu et al, 1993).…”

Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein

“…The E2F transcription factor, in turn, is regulated by the retinoblastoma family of growth-inhibitory proteins. This family consists of three members: the retinoblastoma protein (pRb) and the related p107 and p130 (Hannon et al, 1993;Li et al, 1993b;Zhu et al, 1993;Weinberg, 1995). Collectively, these proteins are known as the`pocket' proteins, as they have a domain, named the pocket, with which they can bind and inactivate several cellular proteins.…”