P27Kip1 in Myc-induced Apoptosis and Lymphomagenesis

St. Jude Children'S Research Hospital, Memphis TN

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Abstract

DESCRIPTION (provided by applicant): The long term goal of this research is to determine the mechanisms by which Myc induces apoptosis and examine how these apoptotic pathways are bypassed during tumorigenesis. We have established that c-Myc activation triggers two apoptotic pathways. First, Myc induces the sustained expression of ARF a nucleolar tumor suppressor that activates p53-dependent apoptosis. Second, our findings have established that the observed synergism between Myc and the anti-apoptotic protein Bcl-2 in transforming hematopoietic cells reflects a Myc-induced apoptotic pathway that normally selectively suppresses the expression of Bcl-2 or Bcl-XL. Furthermore, the suppression of Bcl-2 or Bcl-XL by Myc is corrupted during Myc-induced tumorigenesis, as Bcl-2 and/or Bcl- XL levels are markedly elevated in 60% of lymphomas that arise in E mu-myc transgenic mice. Myc suppresses Bcl- XL and Bcl-2 independent of ARF or p53 status and Bcl-2 and/or Bcl-XL overexpression does not correlate with loss of ARF or p53 function in tumor cells, nor with Mdm2 overexpression. This suggests that these two apoptotic pathways are inactivated independently. We have now discovered that there are links between the ability of Myc to downregulate the cyclin dependent kinase inhibitor p27 Kip1 and to suppress the expression of Bcl-2. Therefore, the specific goal of this proposal is to determine the role of the p27 Kip1 pathway in Myc's ability to induce apoptosis and promote lymphomagenesis, and to suppress Bcl-2 or BcI-XL expression.