Proteasomal Turnover of p21Cip1 Does Not Require p21Cip1 Ubiquitination

Sheaff, Robert J.; Singer, Jeffrey D.; Swanger, Jherek; Smitherman, Matthew; Roberts, James M.; Clurman, Bruce E.

doi:10.1016/s1097-2765(00)80435-9

Cited by 378 publications

(373 citation statements)

References 38 publications

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“…In addition, p21 stability is known to be regulated by the proteasome (Blagosklonny et al, 1996;Maki and Howley, 1997). Although ubiquitination is a signal for protein degradation, surprisingly, the modification of all six lysines in p21 to arginine did not alter the proteasome-dependent nature of p21 degradation (Sheaff et al, 2000). Instead, p21 was shown to physically interact with the C8 a-subunit of the proteasome and overexpression of mutant forms of p21 unable to bind the proteasome showed greatly enhanced stability.…”

Section: Discussionmentioning

confidence: 99%

hSMG-1 and ATM sequentially and independently regulate the G1 checkpoint during oxidative stress

et al. 2008

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Genotoxic stress activates the phosphatidylinositol 3-kinase-like kinases (PIKKs) that phosphorylate proteins involved in cell cycle arrest, DNA repair and apoptosis. Previous work showed that the PIKK ataxia telangiectasia mutated (ATM) but not ATM and Rad3 related phosphorylates p53 (Ser15) during hyperoxia, a model of prolonged oxidative stress and DNA damage. Here, we show hSMG-1 is responsible for the rapid and early phosphorylation of p53 (Ser15) and that ATM helps maintain phosphorylation after 24 h. Despite reduced p53 phosphorylation and abundance in cells depleted of hSMG-1 or ATM, levels of the p53 target p21 were still elevated and the G 1 checkpoint remained intact. Conditional overexpression of p21 in p53-deficient cells revealed that hyperoxia also stimulates wortmannin-sensitive degradation of p21. siRNA depletion of hSMG-1 or ATM restored p21 stability and the G 1 checkpoint during hyperoxia. These findings establish hSMG-1 as a proximal regulator of DNA damage signaling and reveal that the G 1 checkpoint is tightly regulated during prolonged oxidative stress by both PIKK-dependent synthesis and proteolysis of p21.

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Section: Discussionmentioning

confidence: 99%

hSMG-1 and ATM sequentially and independently regulate the G1 checkpoint during oxidative stress

et al. 2008

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“…It is noteworthy that the C terminus of p21, namely p21 (139-164), which was bound to both C8 a-subunit of 20S proteasome (Touitou et al, 2001) and REGg proteasome activator (Chen et al, 2007), has an essential role in direct degradation of p21 by proteasome (Sheaff et al, 2000;Chen et al, 2007;Li et al, 2007). In addition, there are four lysine residues (K141, K154, K161 and K163) in the C terminus of p21 protein, which raising the possibility that FATS-mediated acetylation might be directly correlated with p21 stabilization.…”

Section: Acetylation Of P21 Suppresses Its Ubiquitin-independent Protmentioning

confidence: 99%

“…In eukaryotic DNA damage signaling pathways, tumor suppressor p53 and its transcriptional target CDKN1A (p21) have an essential role in monitoring cell-cycle checkpoints (Brugarolas et al, 1995;Deng et al, 1995;Bunz et al, 1998). The cell-cycle inhibitor p21 is an unstable protein that is subjected to proteasome-dependent degradation in both ubiquitin-dependent (Bloom et al, 2003;Bendiennat et al, 2003;Coulombe et al, 2004) and ubiquitin-independent manners (Sheaff et al, 2000;Li et al, 2007;Chen et al, 2007). Unbound p21 is directly degraded by proteasome independently of ubiquitination, as the endogenous p21 is fully acetylated at its amino terminus and is therefore not a substrate for N-end rule ubiquitination (Varshavsky et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

Zhang

Mao

et al. 2010

Oncogene

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There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genomewide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.

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“…Proteasomal activity is essential in maintaining low-level basal p21 Cip1/Waf1 protein expression by regulating its degradation. [12][13][14][15] The murine double minute 2 (MDM2) oncogene is amplified and overexpressed in numerous human cancers [16][17][18][19] including Rhabdomyosarcoma (RMS) tumors and cell lines. 20,21 MDM2 negatively regulates p53 transcriptional activity 18,22 and promotes p53 degradation by the proteasome.…”

mentioning

confidence: 99%

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

et al. 2007

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The sphingoplipid ceramide is responsible for a diverse range of biochemical and cellular responses including a putative role in modulating cell cycle progression. Herein, we describe that an accumulation of ceramide, achieved through the exogenous application of C 6 -ceramide or exposure to sphingomyelinase, induces a G 2 arrest in Rhabdomyosarcoma (RMS) cell lines. Utilizing the RMS cell line RD, we show that this G 2 arrest required the rapid induction of p21 Cip1/Waf1 independent of DNA damage. This was followed at later time points (48 h) by the commitment to apoptosis. Apoptosis was prevented by Bcl-2 overexpression, but permitted the maintenance of elevated p21 Cip1/Waf1 protein expression and the stabilization of the G 2 arrest response. Inhibition of p21 Cip1/Waf1 protein synthesis with cyclohexamide (CHX) or silencing of p21 Cip1/Waf1 with siRNA, prevented ceramide-mediated G 2 arrest and the late induction of apoptosis. Further, adopting the recent discovery that murine double minute 2 (MDM2) controls p21 Cip1/Waf1 expression by presenting this CDK inhibitor to the proteasome for degradation, RD cells overexpressing MDM2 abrogated ceramide-mediated p21 Cip1/Waf1 induction, G 2 arrest and the late ensuing apoptosis. Collectively, these data further support the notion that ceramide accumulation can modulate cell cycle progression. Additionally, these observations highlight MDM2 expression and proteasomal activity as key determinants of the cellular response to ceramide accumulation.

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Proteasomal Turnover of p21Cip1 Does Not Require p21Cip1 Ubiquitination

Cited by 378 publications

References 38 publications

hSMG-1 and ATM sequentially and independently regulate the G1 checkpoint during oxidative stress

hSMG-1 and ATM sequentially and independently regulate the G1 checkpoint during oxidative stress

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

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