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Pir2/rnf144b regulates epithelial homeostasis by mediating degradation of p21and p63

Pir2/rnf144b regulates epithelial homeostasis by mediating degradation of p21and p63
Pir2/rnf144b regulates epithelial homeostasis by mediating degradation of p21and p63
?Np63 is a transcription factor that is critical for the development of stratified epithelia and is overexpressed or amplified in >80% of squamous cell carcinomas (SCCs). We identified the RING finger E3 ubiquitin ligase PIR2/Rnf144b as a direct transcriptional target of ?Np63? and showed that its expression parallels that of ?Np63? in keratinocytes, SCC cell lines and SCCs. We used primary keratinocytes as a model system to investigate the function of PIR2/Rnf144b in stratified epithelia. Depletion of PIR2/Rnf144b severely impaired keratinocyte proliferation and differentiation, associated with accumulation of p21WAF1/CIP1; a known target of PIR2/Rnf144b. More importantly, we found that PIR2/Rnf144b binds and mediates proteasomal degradation of ?Np63?, generating a hitherto unknown auto-regulatory feedback loop. These findings substantiate PIR2/Rnf144b as a potentially critical component of epithelial homeostasis, acting downstream of ?Np63? to regulate cellular levels of p21WAF1/CIP1 and ?Np63?
0950-9232
4758-4765
Conforti, F.
d9000d8b-401d-4c0a-84e2-10c3ec2699b1
Yang, A.L.
29fcc8cc-fee8-4cd2-be34-d6c5f2d1862a
Piro, M.C.
db9ebf31-549b-41c4-867f-12a031848dd8
Mellone, Max
7013bff2-2c19-45c4-9ef4-c3aa18799a3d
Terrinoni, A.
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Candi, E.
309b94db-4ec1-4d9f-ba67-e657269a603f
Tucci, P.
8078604e-b9c6-4698-a478-094e19a66356
Thomas, G.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Knight, R.A.
a48d0c42-7876-4bf9-808b-cfe88d5dfb3c
Melino, G.
8704cb29-7407-416a-be51-a7efd06144c9
Sayan, B.
66b30158-8435-43cf-98a4-8228b49aa35f
Conforti, F.
d9000d8b-401d-4c0a-84e2-10c3ec2699b1
Yang, A.L.
29fcc8cc-fee8-4cd2-be34-d6c5f2d1862a
Piro, M.C.
db9ebf31-549b-41c4-867f-12a031848dd8
Mellone, Max
7013bff2-2c19-45c4-9ef4-c3aa18799a3d
Terrinoni, A.
40b4cb46-e0e9-4118-8a8e-4fa8879b4b54
Candi, E.
309b94db-4ec1-4d9f-ba67-e657269a603f
Tucci, P.
8078604e-b9c6-4698-a478-094e19a66356
Thomas, G.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Knight, R.A.
a48d0c42-7876-4bf9-808b-cfe88d5dfb3c
Melino, G.
8704cb29-7407-416a-be51-a7efd06144c9
Sayan, B.
66b30158-8435-43cf-98a4-8228b49aa35f

Conforti, F., Yang, A.L., Piro, M.C., Mellone, Max, Terrinoni, A., Candi, E., Tucci, P., Thomas, G., Knight, R.A., Melino, G. and Sayan, B. (2012) Pir2/rnf144b regulates epithelial homeostasis by mediating degradation of p21and p63. Oncogene, 32, 4758-4765. (doi:10.1038/onc.2012.497). (PMID:23128396)

Record type: Article

Abstract

?Np63 is a transcription factor that is critical for the development of stratified epithelia and is overexpressed or amplified in >80% of squamous cell carcinomas (SCCs). We identified the RING finger E3 ubiquitin ligase PIR2/Rnf144b as a direct transcriptional target of ?Np63? and showed that its expression parallels that of ?Np63? in keratinocytes, SCC cell lines and SCCs. We used primary keratinocytes as a model system to investigate the function of PIR2/Rnf144b in stratified epithelia. Depletion of PIR2/Rnf144b severely impaired keratinocyte proliferation and differentiation, associated with accumulation of p21WAF1/CIP1; a known target of PIR2/Rnf144b. More importantly, we found that PIR2/Rnf144b binds and mediates proteasomal degradation of ?Np63?, generating a hitherto unknown auto-regulatory feedback loop. These findings substantiate PIR2/Rnf144b as a potentially critical component of epithelial homeostasis, acting downstream of ?Np63? to regulate cellular levels of p21WAF1/CIP1 and ?Np63?

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Published date: November 2012
Organisations: Cancer Sciences

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Local EPrints ID: 359555
URI: https://eprints.soton.ac.uk/id/eprint/359555
ISSN: 0950-9232
PURE UUID: 0e09524a-0133-40ab-a9a9-1a86755391bf

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Date deposited: 04 Nov 2013 14:19
Last modified: 18 Jul 2017 03:20

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Contributors

Author: F. Conforti
Author: A.L. Yang
Author: M.C. Piro
Author: Max Mellone
Author: A. Terrinoni
Author: E. Candi
Author: P. Tucci
Author: G. Thomas
Author: R.A. Knight
Author: G. Melino
Author: B. Sayan

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