Figure 2.

The ubiquitin-proteasome system maintains the balance between quiescence, self-renewal, and differentiation of HSCs.

(A) The E3 ligases Itch, SCF^Fbxw7,CBL and SCF^Skp2 maintain the quiescence of the HSC by targeting Notch, c-Myc, and STAT5, among others. (B) Loss of any of those E3 ligases results in self-renewal factor upregulation. As a consequence, HSCs re-enter the cell cycle and divide. The aberrant expansion of HSCs results in hematopoietic exhaustion or leukemia. (C) HSCs need HIF-1α in order to survive in the hypoxic niche. However, during differentiation, they migrate out of the niche. The E3 ligases VHL and MDM2 play an important role in the adaptation to the new environment. HIF-1α must be degraded by VHL for migration and differentiation to occur. Additionally, as increase in ROS activates the p53 pathway, MDM2 controls the levels of p53, promoting cell survival. Impaired activity of USP1, VHL, or MDM2 alters HSC self-renewal and differentiation capacities, resulting in hematopoietic failure. (D) During HSC self-renewal, the DUB USP1 promotes the activation of FANCD2, which is essential for DNA damage repair upon replicative stress.