Oct‐1 is involved in the transcriptional repression of the p15^INK4b gene

Abstract

p15INK4b functions as a tumor suppressor and implicated in cellular senescence. Here, we show that the Oct-1 binding site in the human p15INK4b gene promoter functions as a silencer. Oct-1 specifically interacts with this binding site in vitro and in vivo and SMRT and HDAC 1 are present in the p15INK4b proximal promoter region. Moreover, mouse embryo fibroblasts (MEFs) lacking Oct-1 have shown significantly increased levels of p15INK4b protein compared to their normal counterparts. Treatment with a histone deacetylase (HDAC) inhibitor has activated the expression of p15INK4b in wild-type MEFs but has no effect in MEFs lacking Oct-1, suggesting that Oct-1 represses p15INK4b gene expression in an HDAC-dependent manner. Finally, we show that the expression of Oct-1 protein significantly decreases, whereas p15INK4b protein significantly increases with the cellular aging process. Taken together, these results suggest that Oct-1 is an important transcriptional repressor for p15INK4b gene and the transcriptional repression of the p15INK4b gene by Oct-1 may be one of the regulatory mechanisms of cellular senescence.

Genetic Variants on Chromosome 15q25 Associated with Lung Cancer Risk in Chinese Populations

“…This effect may result from reduced ability of the rs6495309C allele to bind Oct-1, a transcriptional factor that has been shown to be able to repress gene transcription (23)(24)(25). Consistent with this finding, our results showed that the reporter gene constructs containing the rs6495309C allele had a notably lower promoter activity compared with the constructs without rs6495309C allele.…”

A general mechanism for transcription regulation by Oct1 and Oct4 in response to genotoxic and oxidative stress

“…5D-F; Supplemental Fig. 2 (Hitomi et al 2007), Cyclin D1 (Magne et al 2003), GADD45a and GADD45g (Takahashi et al 2001;Boyer et al 2005), C-reactive protein (Voleti and Agrawal 2005), iNOS (Kim et al 1999), PDRG , and a number of interleukins (Pfeuffer et al 1994;Duncliffe et al 1997;Wu et al 1997;Murayama et al 2006). Recent studies have also identified a global association between Oct1 recognition sequences and stress response regulation.…”

The essence of senescence: Figure 1.

“…One of its primary activators, p16 INK4A , is commonly induced in senescent cells in many contexts in vitro (Serrano et al 1997;Campisi 2005). Other proteins in the p16 INK4A -RB and p53 pathways, notably p21 CIP1 and p15 INK4B , also often accumulate in senescent cells, and have been used as markers reflecting the activation of these pathways in senescence (Alcorta et al 1996;Hara et al 1996;Reznikoff et al 1996;Serrano et al 1997;Erickson et al 1998;Lin et al 1998;Robles and Adami 1998;Zhu et al 1998;Hitomi et al 2007). Induction of p16 INK4A is commonly seen in senescent mouse and human lesions in vivo also (te Poele et al 2002;Collado et al 2005;Michaloglou et al 2005;Gray-Schopfer et al 2006;Dhomen et al 2009;Goel et al 2009), while p53 and p21 CIP1 induction can be evident, too; for example, in senescent mouse prostate tumors .…”