Rb Function in the Apoptosis and Senescence of Non-Neuronal and Neuronal Cells: Role in Oncogenesis

Abstract

Regulators of the cell cycle machinery play a major role in modulating a variety of cellular phenomena including proliferation, quiescence, differentiation, senescence and apoptosis. Studies in the past decade have clearly established a role for the retinoblastoma tumor suppressor protein, Rb, and its primary downstream target E2F1, in the above processes. While the role of the Rb protein in the regulation of cell cycle progression has been analyzed in great detail, its potential roles in apoptosis as well as senescence are relatively less studied. It has become increasingly clear that the anti-apoptotic functions of Rb contribute significantly to the genesis and progression of tumors. This is especially relevant in neuronal systems, since terminally differentiated neurons do not proliferate; therefore the normal anti-proliferative functions of Rb in neurons are not very dominant. This chapter describes the current thoughts on the role of Rb function in the apoptosis and senescence of cells, both of neuronal and non-neuronal origin. Recent studies have also addressed how Rb function is differentially modulated by proliferative and apoptotic signals received at the cell surface, though both lead to Rb inactivation. The contribution of Rb to inducing cellular senescence has been long recognized, but the underlying molecular mechanisms are being elucidated only recently; the contribution of this function of Rb to tumor suppression remains to be understood in detail. It can be expected that an understanding of Rb function in cellular apoptosis and senescence will enhance our ability to develop novel agents and strategies to combat cancer.

Dual Regulation by Pairs of Cyclin-Dependent Protein Kinases and Histone Deacetylases Controls G1 Transcription in Budding Yeast

“…In certain environments, Pcl-Pho85 may have more dramatic, condition-specific effects on Whi5 function than Cdc28 analogous, perhaps, to the regulation of Rb that is required for quiescence and prevention of apoptosis [72],[73]. Previous studies indicate that Whi5 localizes to nuclei in stationary phase cells suggesting that Whi5 may also play a role in G0 [13].…”

“…Recombinant GST-Pcl1 and GST-Whi5 were produced in a BL21 bacterial expression strain; other recombinant proteins were produced in insect cells infected with Baculovirus expression vectors [11],[46],[73]. Proteins were detected with 9E10 anti-Myc, 12C5 anti-HA, and M2 anti-FLAG monoclonal antibodies.…”

Small molecule regulators of Rb–E2F pathway as modulators of transcription

“…In addition to proliferative signals, it has been found that Rb is also phosphorylated upon apoptotic signaling and this can overcome the anti-apoptotic functions of Rb [14, 28, 29]. Thus, stimulation of cell with agents like TNFα or Fas ligand or an anti-Fas antibody led to a significant phosphorylation of Rb, leading to its inactivation [28, 30].…”

“…Our laboratory has been interested in studying the mechanisms by which the Rb protein exerts its growth control properties and how inactivation of Rb leads to oncogenesis [14]. The Rb family consists of three genes, Rb, p107 and p130 [15]; of these, only Rb has been found to be mutated in a wide array of tumors [8, 16].…”

p53 and Cell Cycle Proteins Participate in Spinal Motor Neuron Cell Death in ALS~!2010-02-16~!2010-02-19~!2010-04-14~!

“…Cell cycle components such as ppRb, E2F and p53 function in both cell cycle progression and apoptosis [1-3]. In fact the promoters of p53, p73, human cytochrome c1 and apoptotic protease activating factor 1 (APAF1) contain E2F-1 binding sites suggesting an E2F-1-mediated transcriptional regulation [3-6].…”