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Structure and apoptotic function of p73.

Yoon MK, Ha JH, Lee MS, Chi SW - BMB Rep (2015)

Bottom Line: Like p53, p73 induces apoptosis and cell cycle arrest and transactivates p53-responsive genes, conferring its tumor suppressive activity.In addition, p73 has unique roles in neuronal development and differentiation.In this review, we discuss the p73 structures reported to date, detailed structural comparisons between p73 and p53, and current understanding of the transcription-dependent and -independent mechanisms of p73-induced apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Structural Biology & Nanopore Research Laboratory, Functional Genomics Research Center, KRIBB, Daejeon 305-806, Korea.

ABSTRACT
p73 is a structural and functional homologue of the p53 tumor suppressor protein. Like p53, p73 induces apoptosis and cell cycle arrest and transactivates p53-responsive genes, conferring its tumor suppressive activity. In addition, p73 has unique roles in neuronal development and differentiation. The importance of p73-induced apoptosis lies in its capability to substitute the pro-apoptotic activity of p53 in various human cancer cells in which p53 is mutated or inactive. Despite the great importance of p73-induced apoptosis in cancer therapy, little is known about the molecular basis of p73-induced apoptosis. In this review, we discuss the p73 structures reported to date, detailed structural comparisons between p73 and p53, and current understanding of the transcription-dependent and -independent mechanisms of p73-induced apoptosis.

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Related in: MedlinePlus

Proposed mechanism for transcription-dependent p73-induced apoptosis. In response to cellular stress, the pro-apoptotic, transcriptionally active p73 (TAp73) isoform transactivates pro-apoptotic genes such as Bax and GRAMD4 and apoptin, whereas the anti-apoptotic transcriptionally inactive p73 (DNp73) isoform inhibits the pro-apoptotic activity of TAp73. In turn, overexpressed pro-apoptotic proteins act directly on the mitochondria to trigger apoptosis. For the extrinsic apoptotic pathway, apoptosis is initiated upon binding of CD95-L to the CD95 death receptor, induced by p73. The apoptotic activity of nuclear p73 is indirect via these mechanisms. Dotted arrows indicate the activation pathway for the viral protein apoptin and the solid arrows designate the pathways for other human proteins.
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Figure 003: Proposed mechanism for transcription-dependent p73-induced apoptosis. In response to cellular stress, the pro-apoptotic, transcriptionally active p73 (TAp73) isoform transactivates pro-apoptotic genes such as Bax and GRAMD4 and apoptin, whereas the anti-apoptotic transcriptionally inactive p73 (DNp73) isoform inhibits the pro-apoptotic activity of TAp73. In turn, overexpressed pro-apoptotic proteins act directly on the mitochondria to trigger apoptosis. For the extrinsic apoptotic pathway, apoptosis is initiated upon binding of CD95-L to the CD95 death receptor, induced by p73. The apoptotic activity of nuclear p73 is indirect via these mechanisms. Dotted arrows indicate the activation pathway for the viral protein apoptin and the solid arrows designate the pathways for other human proteins.

Mentions: The capability of p73 to induce apoptosis is generally attributed to the transactivation of pro-apoptotic genes by p73. p73-responsive target genes include PUMA and Bax (classical pro-apoptotic Bcl-2 family members) as well as the recently identified GRAMD4 and viral protein apoptin in an intrinsic apoptotic pathway and the death receptor CD95 in an extrinsic apoptotic pathway. In these mechanisms, p73 indirectly induces apoptosis within the nucleus by transactivating the genes, enabling them to act in the mitochondria or cytoplasm (Fig. 3).


Structure and apoptotic function of p73.

Yoon MK, Ha JH, Lee MS, Chi SW - BMB Rep (2015)

Proposed mechanism for transcription-dependent p73-induced apoptosis. In response to cellular stress, the pro-apoptotic, transcriptionally active p73 (TAp73) isoform transactivates pro-apoptotic genes such as Bax and GRAMD4 and apoptin, whereas the anti-apoptotic transcriptionally inactive p73 (DNp73) isoform inhibits the pro-apoptotic activity of TAp73. In turn, overexpressed pro-apoptotic proteins act directly on the mitochondria to trigger apoptosis. For the extrinsic apoptotic pathway, apoptosis is initiated upon binding of CD95-L to the CD95 death receptor, induced by p73. The apoptotic activity of nuclear p73 is indirect via these mechanisms. Dotted arrows indicate the activation pathway for the viral protein apoptin and the solid arrows designate the pathways for other human proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4352617&req=5

Figure 003: Proposed mechanism for transcription-dependent p73-induced apoptosis. In response to cellular stress, the pro-apoptotic, transcriptionally active p73 (TAp73) isoform transactivates pro-apoptotic genes such as Bax and GRAMD4 and apoptin, whereas the anti-apoptotic transcriptionally inactive p73 (DNp73) isoform inhibits the pro-apoptotic activity of TAp73. In turn, overexpressed pro-apoptotic proteins act directly on the mitochondria to trigger apoptosis. For the extrinsic apoptotic pathway, apoptosis is initiated upon binding of CD95-L to the CD95 death receptor, induced by p73. The apoptotic activity of nuclear p73 is indirect via these mechanisms. Dotted arrows indicate the activation pathway for the viral protein apoptin and the solid arrows designate the pathways for other human proteins.
Mentions: The capability of p73 to induce apoptosis is generally attributed to the transactivation of pro-apoptotic genes by p73. p73-responsive target genes include PUMA and Bax (classical pro-apoptotic Bcl-2 family members) as well as the recently identified GRAMD4 and viral protein apoptin in an intrinsic apoptotic pathway and the death receptor CD95 in an extrinsic apoptotic pathway. In these mechanisms, p73 indirectly induces apoptosis within the nucleus by transactivating the genes, enabling them to act in the mitochondria or cytoplasm (Fig. 3).

Bottom Line: Like p53, p73 induces apoptosis and cell cycle arrest and transactivates p53-responsive genes, conferring its tumor suppressive activity.In addition, p73 has unique roles in neuronal development and differentiation.In this review, we discuss the p73 structures reported to date, detailed structural comparisons between p73 and p53, and current understanding of the transcription-dependent and -independent mechanisms of p73-induced apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Structural Biology & Nanopore Research Laboratory, Functional Genomics Research Center, KRIBB, Daejeon 305-806, Korea.

ABSTRACT
p73 is a structural and functional homologue of the p53 tumor suppressor protein. Like p53, p73 induces apoptosis and cell cycle arrest and transactivates p53-responsive genes, conferring its tumor suppressive activity. In addition, p73 has unique roles in neuronal development and differentiation. The importance of p73-induced apoptosis lies in its capability to substitute the pro-apoptotic activity of p53 in various human cancer cells in which p53 is mutated or inactive. Despite the great importance of p73-induced apoptosis in cancer therapy, little is known about the molecular basis of p73-induced apoptosis. In this review, we discuss the p73 structures reported to date, detailed structural comparisons between p73 and p53, and current understanding of the transcription-dependent and -independent mechanisms of p73-induced apoptosis.

Show MeSH
Related in: MedlinePlus