PML regulates PER2 nuclear localization and circadian function

Abstract

Studies have suggested that the clock regulator PER2 is a tumour suppressor. A cancer network involving PER2 raises the possibility that some tumour suppressors are directly involved in the mammalian clock. Here, we show that the tumour suppressor promyelocytic leukaemia (PML) protein is a circadian clock regulator and can physically interact with PER2. In the suprachiasmatic nucleus (SCN), PML expression and PML-PER2 interaction are under clock control. Loss of PML disrupts and dampens the expression of clock regulators Per2, Per1, Cry1, Bmal1 and Npas2. In the presence of PML and PER2, BMAL1/CLOCK-mediated transcription is enhanced. In Pml À/À SCN and mouse embryo fibroblast cells, the cellular distribution of PER2 is primarily perinuclear/ cytoplasmic. PML is acetylated at K487 and its deacetylation by SIRT1 promotes PML control of PER2 nuclear localization. The circadian period of Pml À/À mice displays reduced precision and stability consistent with PML having a role in the mammalian clock mechanism.

High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance inCry-deficient mice

“…Finally, Per2 Ϫ/Ϫ mice have been recently reported to have increased glucosestimulated insulin secretion (GSIS) (59), contrary to what has been reported for Clock ⌬19 and Bmal1 Ϫ/Ϫ mice (33,43). One could argue that the PER proteins are not ideal representatives of the negative arm, since they appear to predominately moderate the timing of the negative feedback rather than directly inhibiting CLOCK and BMAL1 (25,35), whereas CRY proteins are much stronger inhibitors of E-box-mediated transcription (19,46). The effect of Cry deficiency on metabolism has not yet been investigated.…”

Impaired cognitive function and reduced anxiety‐related behavior in a promyelocytic leukemia (PML) tumor suppressor protein‐deficient mouse

“…The generation of PML null mice (129/Sv-Pmltm1Ppp [Pml −/− ]; 129S3 [as per Festing et al 1999]) has been previously described (Wang et al 1998;Miki et al 2012). For these studies male Pml −/− mice and wild type controls (Pml +/+ ), both in the same genetic background (129/Svev), were used.…”

Dynamics of the circadian clock protein PERIOD2 in living cells

“…In addition, although PER and CRY proteins can localize to the nucleus even in the absence of one another, binding to CRY promotes nuclear accumulation and stabilization of PER proteins (Kume et al, 1999;Miyazaki et al, 2001;Yagita et al, 2002). Moreover, the CoRNR site of PER2, a binding motif for nuclear receptors, and the promyelotic leukemia protein PML have both been reported to be important for nuclear entry (Albrecht et al, 2007;Miki et al, 2012).…”