Regulation of Hematopoietic Cell Engraftment and Myeloid Differentiation by the E3 Ubiquitin Ligase F-Box Protein SKP2,
2011
Abstract 3397 The precise molecular mechanisms that coordinate, at cellular level, the cell fate decisions of self-renewal and differentiation during normal adult hematopoiesis are not yet well defined. SKP2 protein is necessary for ubiquitination and degradation of several cell cycle inhibitors, such as p27 Kip1 , p21 Cip1 and p57 Kip2 . SKP2 overexpression causes quiescent cells to enter the cell cycle and its downregulation is critical for cell cycle arrest. SCF SKP2 is undoubtedly the major ubiquitin ligase regulating the abundance of cell cycle regulatory proteins at the G 1 -S transition. Thus, we sought to explore its role in regulating cell cycle entry of hematopoietic cells. By using a mouse model of SKP2 deletion, we show that SKP2 inactivation retards entry of HSC and progenitors into cell cycle, resulting in enhanced HSC quiescence, increased pool size and increased HSC maintenance. These effects were accompanied by increased cellular levels of p27 Kip1 , p21 Cip1 and p57 Kip2 in HSC and progenitors. Competitive repopulation assays and serial bone marrow (BM) transplantations showed that loss of SKP2 improved hematopoietic engraftment at long-term. Conversely, the slower cell cycle entry induced by SKP2 deletion greatly impaired hematopoietic engraftment at short-term. We also analyzed the effect of SKP2 deletion on myeloid differentiation. Although the loss of SKP2 did not affect significantly the representation of Gr1+Mac1+ cells in the BM of SKP2 null mice at steady-state, SKP2 null BM lineage negative cells showed an accelerated myeloid differentiation in vitro. Similar results were obtained by using a shRNA anti-SKP2. This effect required p27 Kip1 expression, as deletion of SKP2 did not increased differentiation in a p27 Kip1 null background, and was, surprisingly, cell cycle-independent. Taken together, these results demonstrate a previously unrecognized role for SKP2 in regulating rates of hematopoietic engraftment and myeloid differentiation in the BM. The identification of SKP2 as a physiologic regulator of cell cycle progression of HSC and progenitors has significant implications in the biology of hematopoietic stem cells. We believe that these results may contribute to a better understanding of the dynamics of hematopoietic recovery during BM transplantation, as well as of the mechanisms involved in the HSC exhaustion driving BM failure syndromes and may provide new insights for therapeutic applications. Disclosures: No relevant conflicts of interest to declare.
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