Intranuclear 3'-phosphoinositide metabolism and Akt signaling: new mechanisms for tumorigenesis and protection against apoptosis?
Lipid second messengers, particularly those derived from the polyphosphoinositide metabolism, play a pivotal role in multiple cell signaling networks. Phosphoinositide 3-kinase (PI3K) generate 3'-phosphorylated inositol lipids that are key players in a multitude of cell functions. One of the best characterized targets of PI3K lipid products is the serine/threonine protein kinase Akt (protein kinase B, PKB). Recent findings have implicated the PI3K/Akt pathway in tumorigenesis because it stimulates cell proliferation and suppresses apoptosis. However, it was thought that this signal transduction network would exert its carcinogenetic effects mainly by operating in the cytoplasm. Evidence accumulated over the past 15 years has highlighted the presence of an autonomous nuclear inositol lipid cycle, and strongly suggests that lipid molecules are important components of signaling pathways operating at the nuclear level. PI3K, its lipid product phosphatidylinositol (3,4,5) trisphosphate (PtdIns(3,4,5)P3), and Akt have been identified within the nucleus and recent data suggest that they counteract apoptosis also by operating in this cell compartment through a block of caspase-activated DNase and inhibition of chromatin condensation. In this review, we shall summarize the most updated and intriguing findings about nuclear PI3K/PtdIns(3,4,5)P3/Akt in relationship with tumorigenesis and suppression of apoptotic stimuli.
Martelli
Alberto M
AM
Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia Umana, Cell Signalling Laboratory, Università di Bologna, via Irnerio 48, 40126 Bologna, Italy. amartell@biocfarm.unibo.it
Faenza
Irene
I
Billi
Anna Maria
AM
Manzoli
Lucia
L
Evangelisti
Camilla
C
Falà
Federica
F
Cocco
Lucio
L
D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
D010716:Phosphatidylinositols; D051057:Proto-Oncogene Proteins c-akt