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Sci. Signal., 26 June 2012
Vol. 5, Issue 230, p. ra46
[DOI: 10.1126/scisignal.2002796]

RESEARCH ARTICLES

Selective Effects of PD-1 on Akt and Ras Pathways Regulate Molecular Components of the Cell Cycle and Inhibit T Cell Proliferation

Nikolaos Patsoukis1*, Julia Brown1*, Victoria Petkova1, Fang Liu2, Lequn Li1, and Vassiliki A. Boussiotis1{dagger}

1 Department of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
2 Center for Advanced Biotechnology and Medicine and Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA.

* These authors contributed equally to this work.

Abstract: The receptor programmed death 1 (PD-1) inhibits T cell proliferation and plays a critical role in suppressing self-reactive T cells, and it also compromises antiviral and antitumor responses. To determine how PD-1 signaling inhibits T cell proliferation, we used human CD4+ T cells to examine the effects of PD-1 signaling on the molecular control of the cell cycle. The ubiquitin ligase SCFSkp2 degrades p27kip1, an inhibitor of cyclin-dependent kinases (Cdks), and PD-1 blocked cell cycle progression through the G1 phase by suppressing transcription of SKP2, which encodes a component of this ubiquitin ligase. Thus, in T cells stimulated through PD-1, Cdks were not activated, and two critical Cdk substrates were not phosphorylated. Activation of PD-1 inhibited phosphorylation of the retinoblastoma gene product, which suppressed expression of E2F target genes. PD-1 also inhibited phosphorylation of the transcription factor Smad3, which increased its activity. These events induced additional inhibitory checkpoints in the cell cycle by increasing the abundance of the G1 phase inhibitor p15INK4 and repressing the Cdk-activating phosphatase Cdc25A. PD-1 suppressed SKP2 transcription by inhibiting phosphoinositide 3-kinase–Akt and Ras–mitogen-activated and extracellular signal–regulated kinase kinase (MEK)–extracellular signal–regulated kinase (ERK) signaling. Exposure of cells to the proliferation-promoting cytokine interleukin-2 restored activation of MEK-ERK signaling, but not Akt signaling, and only partially restored SKP2 expression. Thus, PD-1 blocks cell cycle progression and proliferation of T lymphocytes by affecting multiple regulators of the cell cycle.

{dagger} To whom correspondence should be addressed. E-mail: vboussio{at}bidmc.harvard.edu

Citation: N. Patsoukis, J. Brown, V. Petkova, F. Liu, L. Li, V. A. Boussiotis, Selective Effects of PD-1 on Akt and Ras Pathways Regulate Molecular Components of the Cell Cycle and Inhibit T Cell Proliferation. Sci. Signal. 5, ra46 (2012).

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