Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2002; 98(26):14967-72. DOI: 10.1073/pnas.231467698
Source: PubMed


Transgenic mice expressing MyrAkt from a proximal Lck promoter construct develop thymomas at an early age, whereas transgenic mice expressing constitutively active Lck-AktE40K develop primarily tumors of the peripheral lymphoid organs later in life. The thymus of 6- to 8-week-old MyrAkt transgenic mice is normal in size but contains fewer, larger cells than the thymus of nontransgenic control and AktE40K transgenic mice. Earlier studies had shown that cell size and cell cycle are coordinately regulated. On the basis of this finding, and our observations that the oncogenic potential of Akt correlates with its effect on cell size, we hypothesized that mechanisms aimed at maintaining the size of the thymus dissociate cell size and cell cycle regulation by blocking MyrAkt-promoted G(1) progression and that failure of these mechanisms may promote cell proliferation resulting in an enlarged neoplastic thymus. To address this hypothesis, we examined the cell cycle distribution of freshly isolated and cultured thymocytes from transgenic and nontransgenic control mice. The results showed that although neither transgene alters cell cycle distribution in situ, the MyrAkt transgene promotes G(1) progression in culture. Freshly isolated MyrAkt thymocytes express high levels of cyclins D2 and E and cdk4 but lower than normal levels of cyclin D3 and cdk2. Cultured thymocytes from MyrAkt transgenic mice, on the other hand, express high levels of cyclin D3, suggesting that the hypothesized organ size control mechanisms may down-regulate the expression of this molecule. Primary tumor cells, similar to MyrAkt thymocytes in culture, express high levels of cyclin D3. These findings support the hypothesis that tumor induction is caused by the failure of organ size control mechanisms to down-regulate cyclin D3 and to block MyrAkt-promoted G(1) progression.

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    • "As well, the importance of Akt activity in tumor development induced by loss of PTEN has been reported in a number of studies (Stiles et al., 2002; Bayascas et al., 2005; Chen et al., 2006). Constitutive Akt activation in T cells and thymocytes has been shown to be sufficient to drive autoimmunity and lymphoma (Rathmell et al., 2003) and thymomas (Malstrom et al., 2001), respectively, and bone marrow chimera experiments have demonstrated that enforced expression of constitutively active Akt in HSCs was sufficient for the development of myeloproliferative disease, T cell lymphoma, or AML (Kharas et al., 2010). "
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    ABSTRACT: The generation of lipid products catalyzed by PI3K is critical for normal T cell homeostasis and a productive immune response. PI3K can be activated in response to antigen receptor, co-stimulatory, cytokine, and chemokine signals. Moreover, dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are also regulated by Akt, thus linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN, first identified as a tumor suppressor gene, encodes a lipid phosphatase that, by catalyzing the reverse of the PI3K "reaction," directly opposes PI3K signaling. However, PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling. Through the use of models in which Pten is deleted specifically in T cells, it is becoming increasingly clear that control over autoimmunity and lymphomagenesis by PTEN involves multi-faceted functions of this molecule at multiple stages within the T cell compartment.
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    • "Transcription of the Notch1 locus is likely effected by a number of regulatory factors. In addition to Ikaros and E2A, our preliminary studies indicate a similar aberrant activation of alternative Notch1 promoters in abnormally expanding DP in an activated Akt2 transgenic model (data not shown) (Malstrom et al., 2001). Thus, both nuclear and signaling factors implicated in leukemogenesis may participate in the regulation of this feed-forward loop in Notch signaling. "
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    • "The Lck promoter directs initial expression in T cells just prior to rearrangement of the T-cell receptor (TCR) loci (Perlmutter et al., 1993). Transgenic founder lines expressing high levels of MyrAkt1 developed aggressive thymic lymphomas within 10-20 weeks (Malstrom et al., 2001; Rathmell et al., 2003). T lymphocytes from these mice show increased cell size and proliferation, as well as resistance to apoptosis. "
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