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James A Decaprio - One of the best experts on this subject based on the ideXlab platform.

  • abstract 2538 p53 activation induces cell cycle arrest by promoting dream and rb repression of cell cycle genes
    Cancer Research, 2019
    Co-Authors: Amy E Schade, Martin Fischer, James A Decaprio
    Abstract:

    p53 activation results cell cycle arrest at the G1/S checkpoint and the repression of early (G1/S) and late (G2/M) cell cycle gene expression in a p21 dependent manner. The mechanism how p53 and p21 repress cell cycle gene expression is unclear. p21 is known to repress CDK2 which is a key inhibitor of the Pocket Protein Family members RB and p130. During a normal cell cycle, p130 as part of the DREAM complex (DP1, RB-like p130, E2F4, and MuvB) and RB cooperate to repress expression of early (G1/S) and late (G2/M) cell cycle gene expression. DREAM binds and represses late (G2/M) cell cycle promoters through MuvB binding and early (G1/S) cell cycle promoters though repressor E2F binding. RB is only able to bind and repress early (G1/S) cell cycle promoters through its interaction with activator E2Fs. The requirement for DREAM and RB for control of cell cycle gene expression after p53 activation was unknown. We hypothesized that DREAM and RB would cooperate to repress cell cycle gene expression after DNA damage. Using primary human foreskin fibroblast cells lacking RB and/or p130, we found repression of early and late cell cycle gene expression is differentially regulated after p53 activation. We found that while RB is required for repression of early (G1/S) cell cycle genes after p53 activation, DREAM is required for repression of expression of late (G2/M) cell cycle genes. Surprisingly, DREAM was unable to repress early cell cycle genes after p53 activation, suggesting that RB is the key regulator of G1/S gene expression during cellular stress like DNA damage. Further, the requirement for DREAM to repress late cell cycle gene expression underlies the importance of DREAM to prevent expression of mitosis inducing genes in a state like DNA damage when mitosis could result in propagation of mutated DNA. We found that p107, a Protein reported be able to replace p130 in DREAM, does not potently repress early cell cycle genes in HFFs under contact arrest and serum starvation. However, we found that p107 strongly represses expression of late cell cycle genes during G0 in cells lacking p130 alone or in combination with RB. These data provide evidence for a specific role for p107-DREAM not previously appreciated. Together, our data show that control of cell cycle gene expression after p53 activation is split in two: RB represses early cell cycle genes while DREAM represses late cell cycle genes. Citation Format: Amy E. Schade, Martin Fischer, James A. DeCaprio. p53 activation induces cell cycle arrest by promoting DREAM and RB repression of cell cycle genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2538.

  • a maize cdna encoding a member of the retinoblastoma Protein Family involvement in endoreduplication
    Proceedings of the National Academy of Sciences of the United States of America, 1996
    Co-Authors: Gideon Grafi, Ronald Burnett, Brian A Larkins, James A Decaprio, Tim Helentjaris, William R Sellers, William G Kaelin
    Abstract:

    Retinoblastoma (RB-1) is a tumor suppressor gene that encodes a 105-kDa nuclear phosphoProtein. To date, RB genes have been isolated only from metazoans. We have isolated a cDNA from maize endosperm whose predicted Protein product (ZmRb) shows homology to the "Pocket" A and B domains of the Rb Protein Family. We found ZmRb behaves as a Pocket Protein based on its ability to specifically interact with oncoProteins encoded by DNA tumor viruses (E7, T-Ag, E1A). ZmRb can interact in vitro and in vivo with the replication-associated Protein, RepA, encoded by the wheat dwarf virus. The maize Rb-related Protein undergoes changes in level and phosphorylation state concomitant with endoreduplication, and it is phosphorylated in vitro by an S-phase kinase from endoreduplicating endosperm cells. Together, our results suggest that ZmRb is a representative of the Pocket Protein Family and may play a role in cell cycle progression. Moreover, certain plant monopartite geminiviruses may operate similarly to mammalian DNA viruses, by targeting and inactivating the retinoblastoma Protein, which otherwise induces G1 arrest.

  • E2F-4, a new member of the E2F transcription factor Family, interacts with p107.
    Genes & development, 1994
    Co-Authors: Doron Ginsberg, James A Decaprio, G Vairo, Thomas Chittenden, Z X Xiao, K. L. Wydner, Jeanne B. Lawrence, David M. Livingston
    Abstract:

    The E2F Family of transcription factors has been implicated in the regulation of cell proliferation, and E2F-binding sites are present in the promoters of several growth-regulating genes. E2F Family members are functionally regulated, in part, by complex formation with one or more members of the nuclear Pocket Protein Family, RB, p107, and p130. Pocket Protein regulation of E2F likely contributes to normal cellular growth control. While the three cloned species of E2F, E2F-1, E2F-2, and E2F-3, are known to be targets of RB interaction, no E2F species has yet been shown to be a specific p107 or p130 target. Here, we describe the cloning of a new member of the E2F Family, E2F-4, which forms heterodimers with a member(s) of the DP Family and, unlike some Family members, is present throughout the cell cycle and appears to be a differentially phosphorylated p107-binding partner. p107 binding not only can be linked to the regulation of E2F-4 transcriptional activity, but also to suppression of the ability of E2F-4 to transform an immortalized rodent cell line.

Antonio Giordano - One of the best experts on this subject based on the ideXlab platform.

  • retinoblastoma Protein Family in cell cycle and cancer a review
    Journal of Cellular Biochemistry, 1996
    Co-Authors: Marco G Paggi, Alfonso Baldi, Francesco Bonetto, Antonio Giordano
    Abstract:

    Two genes, p107 and Rb2/p130, are strictly related to RB, the most investigated tumor suppressor gene, responsible for susceptibility to retinoblastoma. The products of these three genes, namely pRb, p107, and pRb2/p130 are characterized by a peculiar steric conformation, called "Pocket," responsible for most of the functional interactions characterizing the activity of these Proteins in the homeostasis of the cell cycle. The interest in these genes and Proteins springs from their ability to regulate cell cycle processes negatively, being able, for example, to dramatically slow down neoplastic growth. So far, among these genes, only RB is firmly established to act as a tumor suppressor, because its lack-of-function is clearly involved in tumor onset and progression. It has been found deleted or mutated in most retinoblastomas and sarcomas, but its inactivation is likely to play a crucial role in other types of human cancers. The two other members of the Family have been discovered more recently and are currently under extensive investigation. We review analogies and differences among the Pocket Protein Family members, in an attempt to understand their functions in normal and cancer cells.

Peter Loidl - One of the best experts on this subject based on the ideXlab platform.

  • in vitro phosphorylation and acetylation of the murine Pocket Protein rb2 p130
    PLOS ONE, 2012
    Co-Authors: Muhammad Saeed, Florian Schwarze, Adele Loidl, Joachim Meraner, Markus Lechner, Peter Loidl
    Abstract:

    The retinoblastoma Protein (pRb) and the related Proteins Rb2/p130 and 107 represent the “Pocket Protein” Family of cell cycle regulators. A key function of these Proteins is the cell cycle dependent modulation of E2F-regulated genes. The biological activity of these Proteins is controlled by acetylation and phosphorylation in a cell cycle dependent manner. In this study we attempted to investigate the interdependence of acetylation and phosphorylation of Rb2/p130 in vitro. After having identified the acetyltransferase p300 among several acetyltransferases to be associated with Rb2/p130 during S-phase in NIH3T3 cells in vivo, we used this enzyme and the CDK4 Protein kinase for in vitro modification of a variety of full length Rb2/p130 and truncated versions with mutations in the acetylatable lysine residues 1079, 128 and 130. Mutation of these residues results in the complete loss of Rb2/p130 acetylation. Replacement of lysines by arginines strongly inhibits phosphorylation of Rb2/p130 by CDK4; the inhibitory effect of replacement by glutamines is less pronounced. Preacetylation of Rb2/p130 strongly enhances CDK4-catalyzed phosphorylation, whereas deacetylation completely abolishes in vitro phosphorylation. In contrast, phosphorylation completely inhibits acetylation of Rb2/p130 by p300. These results suggest a mutual interdependence of modifications in a way that acetylation primes Rb2/p130 for phosphorylation and only dephosphorylated Rb2/p130 can be subject to acetylation. Human papillomavirus 16-E7 Protein, which increases acetylation of Rb2/p130 by p300 strongly reduces phosphorylation of this Protein by CDK4. This suggests that the balance between phosphorylation and acetylation of Rb2/p130 is essential for its biological function in cell cycle control.

Wolfgang Bohn - One of the best experts on this subject based on the ideXlab platform.

  • rb2 p130 is the dominating Pocket Protein in the p53 p21 dna damage response pathway leading to senescence
    Oncogene, 2009
    Co-Authors: Heike Helmbold, N Komm, Wolfgang Deppert, Wolfgang Bohn
    Abstract:

    The different Pocket Proteins are established as negative cell cycle regulators. With regard to the repressor functions of Pocket Proteins in cellular senescence, studies so far have mainly focused on pRb/p105. Here, we show that in a broad range of wild-type p53-expressing human tumor cells, and in human diploid fibroblasts, Rb2/p130 is the dominating Pocket Protein in replicative and in accelerated senescence. Senescent cells are arrested at the transition from late G1- to early S-phase, as indicated by the absence of S- and G2-phase cyclins A and B. Expression of cyclin A and entry into S-phase resumed after RNA interference-mediated knockdown of Rb2/p130. Activation of different upstream pathways by overexpression of either p21 or p16 converged on Rb2/p130 accumulation and induced senescence. In contrast, p53- or p21-negative cells treated with DNA-damaging agents failed to accumulate Rb2/p130 and to enter senescence. Our data suggest that Rb2/p130 is a member of the p53–p21 DNA damage signaling cascade, and represents the essential Pocket Protein Family member needed for the induction of any type of senescence.

Robert L Margolis - One of the best experts on this subject based on the ideXlab platform.

  • multiple centrosomes arise from tetraploidy checkpoint failure and mitotic centrosome clusters in p53 and rb Pocket Protein compromised cells
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Franck Borel, Olivier D Lohez, Francoise B Lacroix, Robert L Margolis
    Abstract:

    A high degree of aneuploidy characterizes the majority of human tumors. Aneuploid status can arise through mitotic or cleavage failure coupled with failure of tetraploid G1 checkpoint control, or through deregulation of centrosome number, thus altering the number of mitotic spindle poles. p53 and the RB Pocket Proteins are important to the control of G1 progression, and p53 has previously been suggested as important to the control of centrosome duplication. We demonstrate here that neither suppression of p53 nor of the RB Pocket Protein Family directly generates altered centrosome numbers in any of several mammalian primary cell lines. Instead, amplification of centrosome number occurs in two steps. The first step is failure to arrest at a G1 tetraploidy checkpoint after failure to segregate the genome in mitosis, and the second step is clustering of centrosomes at a single spindle pole in subsequent tetraploid or aneuploid mitosis. The trigger for these events is mitotic or cleavage failure that is independent of p53 or RB status. Finally, we find that mouse embryo fibroblasts spontaneously enter tetraploid G1, explaining the previous demonstration of centrosome amplification by p53 abrogation alone in these cells.