p14ARF links the tumour suppressors RB and p53

  title={p14ARF links the tumour suppressors RB and p53},
  author={Stewart Bates and Andrew C. Phillips and Paula A. Clark and Francesca J. Stott and Gordon G. Peters and Robert L. Ludwig and Karen H. Vousden},
Most human cancers show perturbation of growth regulation mediated by the tumour-suppressor proteins retinoblastoma (RB) and p53 (ref. 1), indicating that loss of both pathways is necessary for tumour development. Loss of RB function leads to abnormal proliferation related to the deregulation of the E2F transcription factors, but also results in the activation of p53, which suppresses cell growth. Here we show that E2F-1 directly activates expression of the human tumour-suppressor protein… 
Role of the p53-homologue p73 in E2F1-induced apoptosis
Evidence that E2F1 directly activates transcription of TP73, leading to activation of p53-responsive target genes and apoptosis is provided, providing evidence that p73 activation by deregulated E 2F1 activity might constitute a p 53-independent, anti-tumorigenic safeguard mechanism.
p73 in apoptosis
Interestingly, in contrast to TP53, TP73 gives rise to a complex pattern of pro- and antiapoptotic p73 isoforms generated by differential splicing and alternative promoter usage, which argues against p73 being a classical tumour suppressor.
Regulation of p53 downstream genes.
The p53 tumor suppressor is the most commonly mutated gene in human cancer and its activation of expression of a number of target genes including p21WAFI, GADD45, 14-3-3 sigma, bax, Fas/APO1, KILLER/DR5, PIG3, Tsp1, IGF-BP3 and others are reviewed.
Role of the RB tumor suppressor in cancer.
From the existing mouse models discussed above, the authors know that proliferation, cell death and differentiation of distinct tissues are also intimately linked through entrance and exit from the cell cycle, and thus through pRB and p53 pathways.
Role for the p53 homologue p73 in E2F-1-induced apoptosis
It is concluded that activation of p73 provides a means for E2F-1 to induce death in the absence of p53, and the transcription of the p53 homologue p73 is induced.
p19ARF targets certain E2F species for degradation
A broader role for p19ARF is suggested as a tumor suppressor, in which targeting of certain E2F species may cooperate with stimulation of the p53 pathway to counteract oncogenic growth signals.
The paradox of E2F1: Oncogene and tumor suppressor gene
The conclusion from these studies is that E2F1 can function as both oncogene and tumor suppressor gene and that both positive and negative effects on tumorigenesis can be observed whether E 2F1 is absent or overexpressed.
Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics.
It is proposed that monitoring of E2F levels and/or activity is a key component of Arf's ability to respond to inappropriate, but not normal cellular proliferation.
Activation and activities of the p53 tumour suppressor protein
The p53 tumour suppressor protein inhibits malignant progression by mediating cell cycle arrest, apoptosis or repair following cellular stress by inhibiting the MDM2-mediated degradation of p53.
miR-335 directly targets Rb1 (pRb/p105) in a proximal connection to p53-dependent stress response.
It is shown that miR-335 is differentially expressed in human cancer cells and that it tightly regulates the expression of Rb1 (pRb/p105) by specifically targeting a conserved sequence motif in its 3' untranslated region that activates the p53 tumor suppressor pathway.


p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens
The effects of the Rb-deficient state on the development of the ocular lens are described and it is demonstrated that loss of Rb function is associated with unchecked proliferation, impaired expression of differentiation markers, and inappropriate apoptosis in lens fibre cells.