We have previously focused on the function of the c-Myc
oncoprotein, whose deregulation is associated with the
development of many types of human tumors. In normal
cells, however, deregulation of Myc accelerates apoptosis.
We propose that the Myc-accelerated apoptosis pathway
may serve as a feedback control mechanism that protects
an organism from uncontrolled cell cycles and tumorigenesis.
Thus, tumor cells that exhibit deregulation of Myc expression
should have also acquired mutations that inhibit apoptosis.
We showed that overexpression of Bcl-2, deletion of
p53, and activation of growth factor-mediated cell survival
pathway inhibit Myc-accelerated apoptosis. Further studies
led us to uncover the major mechanism by which growth
factors promote cell survival. We showed that the serine/threonine
kinase Akt or Protein Kinase B (PKB) is a major determinant
of cell survival in mammalian cells. By generating mice
that are Akt-deficient we provided genetic evidence
that Akt is required for cell survival in a mammalian
organism. It appears that constitutive activation of
Akt is frequently occurring in human cancers mainly
through inactivation of the tumor suppressor PTEN that
normally downregulates Akt activity. We are currently
investigating the role of Akt in the genesis of cancer.
Akt is also a critical regulator of many metabolic pathways,
including protein synthesis and glucose metabolism.
Thus, a major effort in the lab is devoted to characterization
of Akt knockout (KO) mice and analyzing cells established
from these mice to study the function of Akt in apoptosis,
cell cycle, and cell growth.
Selected Publications:
Nogueira, V., Y. Park, C.-C. Chen, P.-Z. Xu, M.-L. Chen, I. Tonic, T. Unterman, and N. Hay. 2008. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14: 458-470.
Hay, N. 2008. p53 strikes mTORC1 by employing sestrins. Cell Metab 8:184-5.
Bhaskar, P. T., and N. Hay. 2007. The Two TORCs and Akt. Dev Cell 12:487-502.
Ju, X., S. Katiyar, C. Wang, M. Liu, X. Jiao, S. Li, J. Zhou, J. Turner, M. P. Lisanti, R. G. Russell, S. C. Mueller, J. Ojeifo, W. S. Chen, N. Hay, and R. G. Pestell. 2007. Akt1 governs breast cancer progression in vivo. Proc Natl Acad Sci U S A 104:7438-43.
Skeen, J. E., Bhaskar, P. T., Chen, C. C., Chen, W.
S., Peng, X. D., Nogueira, V., Hahn-Windgassen, A.,
Kiyokawa, H., and Hay, N. (2006). Akt deficiency impairs
normal cell proliferation and suppresses oncogenesis
in a p53-independent and mTORC1-dependent manner. Cancer
Cell 10, 269-280.
Chen, M. L., Xu, P. Z., Peng, X., Chen, W. S., Guzman,
G., Yang, X., Di Cristofano, A., Pandolfi, P. P., and
Hay, N. (2006). The deficiency of Akt1 is sufficient
to suppress tumor development in Pten+/- mice. Genes
Dev 20, 1569-1574.
Robey, R. B., and Hay, N. (2006). Mitochondrial hexokinases,
novel mediators of the antiapoptotic effects of growth
factors and Akt. Oncogene 25, 4683-4696.
Hahn-Windgassen, A., Nogueira, V., Chen, C. C., Skeen,
J. E., Sonenberg, N., and Hay, N. (2005). Akt activates
the mammalian target of rapamycin by regulating cellular
ATP level and AMPK activity. J Biol Chem 280, 32081-32089.
Hay, N. (2005). The Akt-mTOR tango and its relevance
to cancer. Cancer Cell 8, 179-183.
Robey, R. B., and Hay, N. (2005). Akt, hexokinase,
mTOR: Targeting cellular energy metabolism for cancer
therapy. Drug Discovery Today, in press.
Robey, R. B., and Hay, N. (2005). Mitochondrial hexokinases:
guardians of the mitochondria. Cell Cycle 4, 654-658.
Majewski N., Nogueira V., Bhaskar P., Coy P. E., Skeen
J.E, Gottlob, K., Chandel N. S., Thompson C. B, Robey
R. B, and Hay, N. 2004. Hexokinase-mitochondria interaction
mediated by Akt is required to inhibit apoptosis in
the presence or absence of Bax and Bak. Mol. Cell 16:
819-830.
Hay N, Sonenberg N. 2004. Upstream and downstream of
mTOR. Genes Dev. 18: 1926- 1945.
Majewski, N., V. Nogueira, R. B. Robey, and N. Hay.
2004. Akt inhibits apoptosis downstream of BID cleavage
via a glucose-dependent mechanism involving mitochondrial
hexokinases. Molec. Cell. Biol. 24:730-740.
Peng, X. D., P. Z. Xu, M. L. Chen, A. Hahn-Windgassen,
J. Skeen, J. Jacobs, D. Sundararajan, W. S. Chen, S.
E. Crawford, K. G. Coleman, and N. Hay. 2003. Dwarfism,
impaired skin development, skeletal muscle atrophy,
delayed bone development, and impeded adipogenesis in
mice lacking Akt1
and Akt2. Genes Dev 17:1352-65.
Kandel, E. S., Skeen J., Majewski, N., Di Cristofano,
A., Pandolfi, P.P, Feliciano CS, Gartel A, and Hay,
N. (2002). Activation of Akt/PKB overcomes G2/M cell
cycle checkpoint following DNA damage. Molec, Cell.
Biol. 22: 7831- 7841.
Chen, W., Xu, P-Z., Gottlob, K., Chen, M-L., Sokol,
K., Shiyanova, T., Roninson, I., Weng, W., Suzuki, R.,
Tobe, K., Kadowaki, T., and Hay, N. (2001). Growth retardation
and increased apoptosis in mice with homozygous disruption
of the akt1 gene. Genes and Development 15: 2203-2208.
Gottlob, K., Majewski, N., Kennedy, S., Kandel, E.,
Robey, R.B., and Hay, N. (2001). Inhibition of early
apoptotic events by Akt/PKB is dependent on the first
committed step of glycolysis and mitochondrial hexokinase.
Genes and Development 15: 1406-1418.
Wert, M., Kennedy, S., Palfrey, H.C., and Hay, N. (2001)
Myc drives apoptosis in PC12 cells in the absence of
Max. Oncogene 20: 3746-3750.
Kokontis, J.M., Wagner, A.J., Liao, S., and Hay, N.
(2001) The transcriptional activation function of p53
is dispensable for and inhibitory of its apoptotic function.
Oncogene 20: 659-668.
Conzen, S.D., Gottlob, K., Kandel, E.S., Khanduri, P.,
Wagner, A.J., O’Leary, M., and Hay, N. (2000)
Induction of Cell Cycle Progression and Acceleration
of Apoptosis Are Two Separable Functions of c-Myc: Transrepression
Correlates with Acceleration of Apoptosis. Molec. Cell.
Biol. 20: 6008-18
Kandel, E.S., and Hay, N. (1999). Multiple regulators
and multiple downstream effectors of the serine/threonine
kinase Akt/PKB. Experimental Cell Res. 253: 210-229.
Kennedy, S.G., Kandel, E.S., Cross, T.K., and Hay, N.
(1999). Akt/PKB inhibits cell death by preventing the
release of cytochrome c from mitochondria. Molec. Cell.
Biol. 19: 5800-5810.
Gingras, A.-C., Kennedy, S.G., O’Leary, M., Sonenberg,
N., and Hay, N. (1998). The repressor of mRNA translation,
4E-BP1, is phosphorylated and inactivated by Akt(PKB)-dependent
signaling pathway. Genes and Development 12: 502-513.
Kennedy, S., Wagner, A.J., Conzen S.D., Jordan, J.,
Bellacosa, A., Tsichlis, P.N., and Hay, N. (1997). PI
3-kinase/Akt(PKB) signaling pathway delivers an anti-apoptotic
signal. Genes and Development 11: 701-713.
Wagner, A.J., Kokontis, J., and Hay, N. (1994) Myc-mediated
apoptosis requires wild type p53 in a manner independent
of cell cycle arrest and the ability of p53 to induce
p21waf1/cip1. Genes and Development 8: 2817-2830.
Wagner, A.J., Small, M.B., and Hay, N. (1993) Myc mediated
apoptosis is blocked by ectopic expression of Bcl2.
Molec. Cell. Biol. 13: 2432-2440.
DesJardins, E. and Hay, N. (1993) Repeated CT-elements
bound by zinc finger proteins control the absolute and
relative activities of the two principal human c-myc
promoters. Molec. Cell. Biol. 13: 5710-5724.
Wagner, A.J., Meyers, C., Laimins, L., and Hay, N. (1993).
c-Myc induces ornithine decarboxylase expression and
activity. Cell Growth & Differentiation 4: 879-883.
Amin, C., Wagner, A.J., and Hay, N. (1993) Sequence-specific
transcriptional activation by Myc and repression by
Max. Molec. Cell. Biol. 13: 383-390.
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