Article

Keeping an eye on retinoblastoma control of human embryonic stem cells

Department of Pediatrics, Stanford Medical School, Stanford, California 94305, USA.
Journal of Cellular Biochemistry (Impact Factor: 3.37). 12/2009; 108(5):1023-30. DOI: 10.1002/jcb.22342
Source: PubMed

ABSTRACT Human embryonic stem cells (hESCs) hold great promise in regenerative medicine. However, before the full potential of these cells is achieved, major basic biological questions need to be addressed. In particular, there are still gaps in our knowledge of the molecular mechanisms underlying the derivation of hESCs from blastocysts, the regulation of the undifferentiated, pluripotent state, and the control of differentiation into specific lineages. Furthermore, we still do not fully understand the tumorigenic potential of hESCs, limiting their use in regenerative medicine. The RB pathway is a key signaling module that controls cellular proliferation, cell survival, chromatin structure, and cellular differentiation in mammalian cells. Members of the RB pathway are important regulators of hESC biology and manipulation of the activity of this pathway may provide novel means to control the fate of hESCs. Here we review what is known about the expression and function of members of the RB pathway in hESCs and discuss areas of interest in this field.

Download full-text

Full-text

Available from: Julien Sage, Aug 10, 2015
0 Followers
 · 
165 Views
  • Source
    • "Notably, no significant change in the growth rate of the 4F-infected MEFs was observed upon Rb knockdown (Figure 2A), as was previously observed in Rb-deficient MEFs (Dannenberg et al., 2000; Sage et al., 2000) (see below). Similarly, there was no change in the S phase fraction in the shRb-infected MEFs, although, at day 6 there was a trend to a longer G2 and shorter G1 (Figures 2B and 2C, Figure S2A), possibly a consequence of increased reprogramming because a shorter G1 correlates with the acquisition of pluripotency (Conklin and Sage, 2009). Annexin V staining did not show a significant difference in apoptosis (Figure 2D, Figure S2B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.
    Cell Stem Cell 01/2015; 16(1). DOI:10.1016/j.stem.2014.10.019 · 22.15 Impact Factor
  • Source
    • "Increasing evidence has implicated this pathway in stemness modulation, initially in plants (Ebel et al., 2004; Wildwater et al., 2005) and subsequently in animals (Liu et al., 2009). Accumulating evidence reinforces the role of pRb in stem cell homeostasis (Conklin and Sage, 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A rise in technologies for epigenetic reprogramming of cells to pluripotency, highlights the potential of understanding and manipulating cellular plasticity in unprecedented ways. Increasing evidence points to shared mechanisms between cellular reprogramming and the carcinogenic process, with the emerging possibility to harness these parallels in future therapeutics. In this review, we present a synopsis of recent work from oncogenic viruses which contributes to this body of knowledge, establishing a nexus between infection, cancer, and stemness.
    Frontiers in Cellular and Infection Microbiology 12/2013; 3:66. DOI:10.3389/fcimb.2013.00066 · 2.62 Impact Factor
  • Source
    • "In mESCs, pRb is permanently inactivated by hyperphosphorylation , leading to constitutive activity of E2F TFs, which in turn allows an R-point-independent short transition through G1 phase (Savatier et al. 1994; Stead et al. 2002). Although differences were observed when compared with mESCs (Conklin and Sage 2009), similar mechanisms are presumed to regulate human ESCs (hESCs). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since their discovery in the early 1990s, microRNAs (miRs) have gone from initially being considered an oddity to being recognized as a level of gene expression regulation that is integral to the normal function of cells and organisms. They are implicated in many if not all biological processes in animals, from apoptosis and cell signaling to organogenesis and development. Our understanding of cell regulatory states, as determined primarily by transcription factor (TF) profiles, is incomplete without consideration of the corresponding miR profile. The miR complement of a cell provides robust and redundant control over the output of hundreds of possible targets for each miR. miRs are common components of regulatory pathways, and in some cases can constitute on-off switches that regulate crucial fate decisions. In this review, we summarize our current knowledge about the biogenesis and regulation of miRs and describe their involvement in the pathways that regulate cell division, pluripotency, and reprogramming to the pluripotent state.
    Genes & development 12/2010; 24(24):2732-41. DOI:10.1101/gad.1982910 · 12.64 Impact Factor
Show more