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SUMMARY:Babraham Lecture - Understanding how the p53 onco-suppressor gene 
 works: hints from the P2X7 ATP receptor - Prof. Francesco Di Virgilio\; Pr
 ofessor of Clinical Pathology\, University of Ferrara\, Italy
DTSTART:20180425T130000Z
DTEND:20180425T140000Z
UID:TALK97060@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:The tumour suppressor p53 has a key role against malignant tra
 nsformation\, mainly by inducing cell-cycle arrest and apoptosis. Over 50%
  of human cancers harbor somatic p53 gene mutations\, and\, in addition to
  sporadic tumors\, inherited heterozygous loss-of-function mutations cause
  Li–Fraumeni syndrome\, which confers a high familial risk to various ty
 pes of cancer (Giorgi et al. 2015). Mice lacking p53 (p53 -/-mice) have be
 en shown to have enhanced susceptibility to spontaneous tumors of various 
 types and a shorter lifespan.\nThe P2X7 receptor (P2X7R) is an ATP-gated p
 lasma membrane ion channel expressed to a very high level by several human
  and mouse malignant tumors.  Basal activation of the P2X7R has a trophic 
 effect on energy metabolism as it enhances both mitochondrial oxidative ph
 osphorylation and aerobic glyclolysis\, thus leading to increased ATP synt
 hesis (Di Virgilio and Adinolfi 2017)..\nP2X7R trophic effects are mediate
 d by increases in the cytoplasmic Ca2+ concentration and  activation of se
 veral key transcription factors (e.g. NFATc1\, NFkB\, HIF-1a) (Adinolfi et
  al. 2009)\, but in addition recent evidence show that the P2X7R itself lo
 calizes to the mitochondria. Thus\, overall\, the P2X7R in cancer cells ha
 s a strong growth-promoting effect. Accordingly\, in vivo administration o
 f pharmacological P2X7R blockers inhibits tumor growth in several experime
 ntal cancer models (Adinolfi et al. 2012).\nWe have recently observed that
  cells isolated from mice lacking p53 (p53-/- mice) display both enhanced 
 P2X7R expression and activity (Giorgi C. et al.\, in preparation). Extensi
 on of these observations to human samples\, showed an inverse correlation 
 between p53 and P2X7R expression.\nWe then crossed p53-/- with P2X7R-/- mi
 ce to generate double p53-/-/P2X7R-/- mice. Genetic deletion of the P2X7R 
 in the p53-/- mice delayed cancer appearance and almost doubled the life s
 pan. The same effect was observed by administering pharmacological P2X7R b
 lockers to the p53-/- mice. Moreover\, P2X7R genetic or pharmacological de
 letion re-establishes sensitivity to cytotoxicity triggered by chemotherap
 y drugs.\nAltogether\, these data suggest that the P2X7R has an oncogene-l
 ike behavior\, and that it plays a major role in the mechanism of action o
 f p53.\n\n\n\nReferences\n\nAdinolfi E\, Callegari MG\, Cirillo M\, Pinton
  P\, Giorgi C\, Cavagna D\, Rizzuto R and Di Virgilio F.  	(2009). J Biol 
 Chem\, 284\, 10120-10128.\nAdinolfi E\, Raffaghello L\, Giuliani AL\, Cava
 zzini L\, Capece M\, Chiozzi P\, Bianchi G\, Kroemer G\, 	Pistoia V and Di
  Virgilio\, F. (2012). Cancer Res\, 72\, 2957-2969.\nDi Virgilio\, F and A
 dinolfi E. (2017). Oncogene\, 36\, 293-303.\nGiorgi C\, Bonora M\, Sorrent
 ino G\, Missiroli S\, Poletti F\, Suski JM\, Galindo RF\, Rizzuto R\, Di 	
 Virgilio F\, Zito E\, Pandolfi PP\, Wieckowski MR\, Mammano F\, Del SG and
  Pinton P. 	(2015). Proc Natl Acad Sci U S A\, 112\, 1779-1784.\n
LOCATION:Babraham - The Cambridge Building\; Petersfield Lecture Theatre
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