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Loss of tumor suppressor RPL5/RPL11 does not induce cell-cycle arrest, but impedes proliferation due to reduced ribosome content and translation capacity: Implications in Diamond Blackfan Anemia

Teng, Teng
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383645029

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
Humans have evolved elaborate mechanisms to activate p53 in response to insults that lead to cancer, including the binding and inhibition of Hdm2 by 60S ribosomal proteins (RPs) RPL5 and RPL11. This same mechanism appears to be activated upon impaired ribosome biogenesis, highlighted by an inherited congenital bone marrow failure syndrome Diamond Blackfan Anemia (DBA), characterized by normochromic macrocytic anemia and heterozygous mutations or deletions involving several ribosomal protein (RP) genes including RPS19, RPS24, RPL35a, RPS17, RPS7, RPS10, RPS26, RPL15, RPL5 and RPL11. As loss of RPL5/RPL11 abrogates ribosome biogenesis and protein synthesis to the same extent as other essential 60S RPs, we reasoned their loss would induce a p53-independent cell-cycle checkpoint. Unexpectedly, we found that their depletion in primary human lung fibroblasts failed to induce cell-cycle arrest, but strongly suppressed cell-cycle progression. We show that the effects on cell-cycle progression stemmed from reduced ribosome content and translational capacity, which suppressed the accumulation of cyclins at the translational level. Thus, unlike other tumor suppressors, RPL5/RPL11 play an essential role in normal cell proliferation, a function cells have evolved to rely on in lieu of a cell-cycle checkpoint. We have further set out to determine whether the same mechanism is applicable in erythroid progenitor cells. We find that levels of p53 status vary greatly within erythroid progenitor cells, as shown by immunohistochemistry (IHC) in a limited number of DBA patient bone marrow biopsy slides. Preliminary studies using erythroid progenitor cells differentiated from RPL11 shRNA infected CD34+ cells revealed a lack of p53 induction, consistent with our observation in primary lung fibroblasts, suggesting a p53 independent mechanism in DBA patients with RPL5/RPL11 mutations.
Chunying Du, Ph.D. (Committee Chair)
Nancy Ratner, Ph.D. (Committee Member)
Yi Zheng, Ph.D. (Committee Member)
George Thomas, Ph.D. (Committee Member)
Michael D. Cole, Ph.D. (Committee Member)
151 p.
Cellular Biology
p53; tumor suppressor; ribosome impairment; cell cycle; translation; Diamond Blackfan Anemia

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Citations

  • Teng, T. (2013). Loss of tumor suppressor RPL5/RPL11 does not induce cell-cycle arrest, but impedes proliferation due to reduced ribosome content and translation capacity: Implications in Diamond Blackfan Anemia [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383645029

    APA Style (7th edition)

  • Teng, Teng. Loss of tumor suppressor RPL5/RPL11 does not induce cell-cycle arrest, but impedes proliferation due to reduced ribosome content and translation capacity: Implications in Diamond Blackfan Anemia. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383645029.

    MLA Style (8th edition)

  • Teng, Teng. "Loss of tumor suppressor RPL5/RPL11 does not induce cell-cycle arrest, but impedes proliferation due to reduced ribosome content and translation capacity: Implications in Diamond Blackfan Anemia." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383645029

    Chicago Manual of Style (17th edition)

ucin1383645029
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This open access ETD is published by University of Cincinnati and OhioLINK.