p63, a p53 Homolog at 3q27–29, Encodes Multiple Products with Transactivating, Death-Inducing, and Dominant-Negative Activities

Yang, Annie; Kaghad, Mourad; Wang, Yunmei; Gillett, Emily; Fleming, Mark D.; Dötsch, Volker; Andrews, Nancy C.; Caput, Daniel; McKeon, Frank

doi:10.1016/s1097-2765(00)80275-0

Cited by 1,903 publications

(2,747 citation statements)

References 35 publications

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“…While p53 was long considered to be unique, recently two p53-related genes were discovered (Kaghad et al, 1997;Osada et al, 1998;Yang et al, 1998). TP73 and TP63 encode proteins with remarkable sequence homology to p53, suggesting that they are also involved in the regulation of cell growth and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Regulation of telomerase activity by the p53 family member p73

Beitzinger

Oswald

Beinoraviciute-Kellner

et al. 2005

Oncogene

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The terminal ends of eukaryotic chromosomes, termed telomeres, progressively shorten during each round of cell division eventually leading cells into senescence. Tumor cells typically overcome this barrier to unlimited proliferation by activation of the human telomerase reverse transcriptase (hTERT) gene. In contrast, in most human somatic cells hTERT expression is tightly repressed by multiple tumor suppressors. Here, we studied the regulation of hTERT by the p53 family member p73. We show that forced expression of p73 or activation of endogenous p73 by E2F1 results in the downregulation of telomerase activity. Vice versa, siRNA-mediated knockdown of p73 induces hTERT expression. Responsiveness to p73 is conferred by Sp1 binding sites within the hTERT core promoter. In tumor cells, p73 isoforms lacking the transactivation domain (DNp73) are frequently overexpressed and believed to function as oncogenes. We show that DNp73 antagonizes the repressive effect of the proapoptotic p53 family members on hTERT expression and, in addition, induces hTERT expression in telomerase-negative cells by interfering with E2F-RB-mediated repression of the hTERT core promoter. These data provide evidence that the p73 gene functions as an important regulator of telomerase activity with implications for embryonic development, cellular differentiation and tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

Regulation of telomerase activity by the p53 family member p73

Beitzinger

Oswald

Beinoraviciute-Kellner

et al. 2005

Oncogene

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“…Introduction p51, also known as p63 or KET, is a homologue of the tumor suppressor and transcription factor p53 (herein referred to as p51) (Osada et al, 1998;Yang et al, 1998). p51 not only resembles p53 structurally but also functionally; it acts as a transcription factor capable of inducing apoptosis and growth arrest.…”

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confidence: 99%

“…First, its mutations are rarely detected in human cancers (Osada et al, 1998;Hagiwara et al, 1999). Second, the p51 gene is tissue specifically transcribed into different isoforms (Osada et al, 1998;Yang et al, 1998), whereas p53 is ubiquitously expressed (Bourdon et al, 2005). Isoforms with a notable distinction are collectively termed as TAp51 isoforms and DNp51 isoforms, generated from two alternative promoters.…”

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confidence: 99%

“…The use of distal promoter generates TAp51 isoforms with transactivation domain (TA domain) in their NH 2 -terminus, capable of transactivating various p53 responsive promoters. The use of the proximal promoter generates DNp51 isoforms with a short peptide substituting for the TA domain, which exert dominant-negative activity against TA isoforms and p53 (Yang et al, 1998;Hibi et al, 2000;Ratovitski et al, 2001;Patturajan et al, 2002;Stiewe et al, 2002;Wu et al, 2003). In addition, both isoforms undergo three alternative splicing events at the COOH-terminus generating six different isoforms (reviewed by Ikawa et al (1999); Yang and McKeon (2000); Mills (2006)).…”

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p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

et al. 2007

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“…Similar to p53, p73 and p63 can form homo-oligomers, bind to canonical p53 DNA-binding sites, modulate the transcription of p53-responsive genes and suppress growth or induce apoptosis when overexpressed in certain human tumors (Jost et al, 1997;Kaghad et al, 1997;Osada et al, 1998;Yang et al, 1998). Each protein also shares significant homology with p53 in its transactivation domain, DNAbinding domain (DBD) and oligomerization domain.…”

Section: Introductionmentioning

confidence: 99%

Kinase activity-independent suppression of p73α by AMP-activated kinase α (AMPKα)

et al. 2008

Oncogene

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Although p73a induces many of the same cellular events as p53, it is structurally distinct from p53 in that it possesses a unique COOH-terminal domain. To dissect the function of this domain, we performed yeast twohybrid screening of a HeLa cDNA library using residues 552-636 of p73a as bait. Among the clones that showed a specific interaction with p73a was AMP-activated protein kinase a (AMPKa). Additional yeast two-hybrid assays indicated that the bc-binding domain of AMPKa is critical for the interaction with p73a. The interaction was further confirmed in vitro by glutathione S-transferase pull-down, and in vivo by immunoprecipitation and immunofluorescence microscopy. Transient coexpression of AMPKa resulted in downregulation of the effect of p73a, but not of p53, on various p53-responsive promoters. Chromatin immunoprecipitation indicated p73a-dependent recruitment of AMPKa to the p21WAF1 promoter. Treatment with 5-aminoimidazole-4-carboxamide ribonucleotide, an agonist of AMPKa, and expression of dominant-negative versions of AMPKa revealed that the repression of p73a was independent of AMPKa kinase activity. In addition, cisplatin-induced growth repression was impaired when AMPKa was overexpressed. Upon the knock down of AMPKa by siRNA, the induction of p21WAF1 by p73a was significantly increased. Taken together, these data indicate that AMPKa specifically regulates p73a by a direct interaction without affecting its phosphorylation status. From these data, we speculate that AMPKa may provide a molecular clue to understand the repressive role of the C-terminus of p73a in transcription and DNA damage response.

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p63, a p53 Homolog at 3q27–29, Encodes Multiple Products with Transactivating, Death-Inducing, and Dominant-Negative Activities

Cited by 1,903 publications

References 35 publications

Regulation of telomerase activity by the p53 family member p73

Regulation of telomerase activity by the p53 family member p73

p53 homologue, p51/p63, maintains the immaturity of keratinocyte stem cells by inhibiting Notch1 activity

Kinase activity-independent suppression of p73α by AMP-activated kinase α (AMPKα)

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