title: Inpp5f is a polyphosphoinositide phosphatase that regulates cardiac hypertrophic responsiveness.
abstract: BACKGROUND
  Cardiac hypertrophy occurs in response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway has previously been strongly associated with hypertrophic signaling in the heart, and with the control of cell size in multiple contexts. This pathway is tightly regulated by many factors, including a host of kinases and phosphatases that function at multiple steps in the signaling cascade. For example, the PTEN (phosphatase and tensin homolog) tumor suppressor protein is a phosphoinositide 3-phosphatase that, by metabolizing phosphatidylinositol 3,4,5-trisphosphate (PtdIns[3,4,5]P(3), PIP3), acts in direct antagonism to growth factor-stimulated PI3K. Inhibition of PTEN leads to cardiomyocyte hypertrophy. Another polyphoinositide phosphatase, inositol polyphosphate-5-phosphatase F (Inpp5f) has recently been implicated in regulation of cardiac hypertrophy. Like PTEN, this phosphatase can degrade PtdIns(3,4,5)P(3) and thus modulates the PI3K/Akt pathway.
  
  
  OBJECTIVE
  To characterize the role of Inpp5f in regulating cardiac hypertrophy.
  
  
  RESULTS
  We generated homozygous Inpp5f knockout mice and cardiac specific Inpp5f overexpression transgenic mice. We evaluated their hearts for biochemical, structural and functional changes. Inpp5f knockout mice have augmented hypertrophy and reactivation of the fetal gene program in response to stress when compared to wild-type littermates. Furthermore, cardiac overexpression of Inpp5f in transgenic mice reduces hypertrophic responsiveness.
  
  
  CONCLUSIONS
  Our results suggest that Inpp5f is a functionally important endogenous modulator of cardiac myocyte size and of the cardiac response to stress.
authors.affiliation: 1154 BRB II, University of Pennsylvania, 421 Curie Blvd, Philadelphia PA 19104. epsteinj@mail.med.upenn.edu.
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhu
authors.forename: Chinmay M
authors.initials: CM
authors.lastname: Trivedi
authors.forename: Diane
authors.initials: D
authors.lastname: Zhou
authors.forename: Lijun
authors.initials: L
authors.lastname: Yuan
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048429:Cell Size; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D007545:Isoproterenol; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D007295:Inositol Phosphates; D012333:RNA, Messenger; C118500:inositol 3,4,5-trisphosphate; D010744:Phosphoric Monoester Hydrolases; C000606431:INPP5F protein, human; D000072181:Inositol Polyphosphate 5-Phosphatases; D007545:Isoproterenol