HSP27 favors ubiquitination and proteasomal degradation of p27 ^Kip1 and helps S-phase re-entry in stressed cells

Stress-inducible HSP27 protects cells from death through various mechanisms. We have recently demonstrated that HSP27 can also enhance the degradation of some proteins through the proteasomal pathway. Here, we show that one of these proteins is the cyclin-dependent kinase (Cdk) inhibitor p27 ^Kip1. The ubiquitination and degradation of this protein that favors progression through the cell cycle was previously shown to involve either a Skp2-dependent mechanism, i.e., at the S-/G₂-transition, or a KPC (Kip1 ubiquitination-promoting complex)-dependent mechanism, i.e., at the G ₀/G₁ transition. In this work, we demonstrate that, in response to serum depletion, p27^Kip1 cellular content first increases then progressively decreases as cells begin to die. In this stressful condition, HSP27 favors p27^Kip1 ubiquitination and degradation by the proteasome. A similar observation was made in response to stress induced by the NO donor glyceryl trinitrate (GTN). HSP27-mediated ubiquitination of p27 ^Kip1 does not require its phosphorylation on Thr¹⁸⁷ or Ser-10, nor does it depend on the SCF^Skp2 ubiquitin ligase E3 complex. It facilitates the G₁/S transition, which suggests that, in stressful conditions, HSP27 might render quiescent cells competent to re-enter the cell cycle.