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Molecular and Cellular Biology, March 2003, p. 1717-1725, Vol. 23, No. 5
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.5.1717-1725.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The N-Terminal 24 Amino Acids of the p55 Gamma Regulatory Subunit of Phosphoinositide 3-Kinase Binds Rb and Induces Cell Cycle Arrest

Xianmin Xia,1,{dagger} Aiwu Cheng,2,{ddagger} Damilola Akinmade,1,3 and Anne W. Hamburger1,3*

Greenebaum Cancer Center,1 Department of Physiology,2 Department of Pathology, University of Maryland, Baltimore, Maryland 212013

Received 13 September 2002/ Returned for modification 22 October 2002/ Accepted 6 December 2002

Although phosphoinositide 3-kinase (PI 3-kinase) is essential for cell cycle progression, the molecular mechanisms that regulate its diverse biological effects are poorly understood. We demonstrate here that Rb, a key regulator of cell cycle progression, associates with p55 kDa (p55{alpha} and p55{gamma}) regulatory subunits of PI 3-kinase in vivo and in vitro. Both confocal microscopy and biochemical analysis demonstrated the presence of p55{gamma} in the nucleus. The 24-amino-acid N-terminal end of p55{gamma}, which is unique among PI 3-kinase regulatory subunits, was sufficient to bind Rb. Addition of serum or growth factors to quiescent cells triggered the dissociation of Rb from p55. Ectopic expression of the 24-amino-acid N-terminal end of p55{gamma} inhibited cell cycle progression, as evidenced by induction of cell growth arrest at the G0/G1 phase, inhibition of DNA synthesis, inhibition of cyclin D and cyclin E promoter activity, and changes in the expression of cell cycle-related proteins. The inhibitory effects of the N-terminal end of p55{gamma} on cell cycle progression depended on the presence of functional Rb. These data demonstrate for the first time an association of p55{gamma} with Rb and show that modification of this association can lead to cell cycle arrest.

* Corresponding author. Mailing address: University of Maryland Greenebaum Cancer Center, 655 W. Baltimore St., Baltimore, MD 21201. Phone: (410) 328-3911. Fax: (410) 328-6559. E-mail: ahamburg{at}som.umaryland.edu.

{dagger} Present address: Protein Tech Group, Chicago, IL 60612.

{ddagger} Present address: Laboratory of Neuroscience, GRC, NIA, NIH, Baltimore, MD 21224.

Molecular and Cellular Biology, March 2003, p. 1717-1725, Vol. 23, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.5.1717-1725.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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