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pRb or its cousins: who controls the family business?
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PMID:  22544076     Owner:  NLM     Status:  MEDLINE    
Koji Itahana; Goberdhan P Dimri
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Publication Detail:
Type:  News    
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-30     Completed Date:  2012-09-14     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1486     Citation Subset:  IM    
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MeSH Terms
Cell Aging
Cell Line, Tumor
Crk-Associated Substrate Protein / metabolism
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Gene Knockdown Techniques
Retinoblastoma Protein / genetics,  metabolism*
Retinoblastoma-Like Protein p107 / metabolism
Grant Support
Reg. No./Substance:
0/BCAR1 protein, human; 0/Crk-Associated Substrate Protein; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Retinoblastoma Protein; 0/Retinoblastoma-Like Protein p107

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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Journal Information
Journal ID (nlm-ta): Cell Cycle
Journal ID (iso-abbrev): Cell Cycle
Journal ID (publisher-id): CC
ISSN: 1538-4101
ISSN: 1551-4005
Publisher: Landes Bioscience
Article Information
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Copyright © 2012 Landes Bioscience
Print publication date: Day: 15 Month: 4 Year: 2012
pmc-release publication date: Day: 15 Month: 4 Year: 2012
Volume: 11 Issue: 8
First Page: 1486 Last Page: 1486
ID: 3342955
PubMed Id: 22544076
Publisher Id: 2012NV0632
Publisher Item Identifier: 20048
DOI: 10.4161/cc.20048

pRb or its cousins : Who controls the family business?
Koji Itahana1
Goberdhan P. Dimri2*
1Cancer & Stem Cell Biology Program; Duke-NUS Graduate Medical School; Singapore
2Department of Biochemistry and Molecular Biology; The George Washington University Medical Center; Washington, DC USA
*Correspondence to: Goberdhan P. Dimri, Email:

More than 90% of human cancers are of epithelial origin. Cellular senescence of human mammary epithelial cells (HMECs) is an important barrier that protects cells from immortalization; the first step in breast cancer development.1 Although induction of tumor suppressor p16 is not evident in some types of normal human fibroblasts undergoing senescence,2 in cultured HMECs, senescence occurs by a robust p16 induction, and cells that acquire silencing of p16Ink4a locus eventually proliferate and undergo senescence again by telomere shortening in a p53-dependent manner.1 Therefore, p16 induction is a critical barrier to immortalize HMECs in culture. p16 inhibits kinase activity of Cdk4/6-cyclinD complexes, which inactivate three pRb family proteins: pRb, p107 and p130. However, the relative contribution of these three pRb family proteins to HMEC senescence is not well understood.

In a recent issue of Cell Cycle, Bazarov et al. examined the role of each pRb family protein in p16-mediated senescence in breast cancer cell lines and in HMECs (Fig. 1).3 They showed that knockdown of each of the three pRb family proteins individually did not abrogate senescence mediated by ectopically expressed p16 in the breast cancer cell lines MDA-MB-231 and MCF7. However, the senescence induced by ectopic p16 was abrogated if they introduced E7, which inactivates all three pRb family proteins. Their data suggest that two of pRb family proteins can compensate for the loss of each pRb family protein to induce p16-mediated senescence in these cancer cells. The remaining question is whether all three pRb family members play an additive role, and whether the inactivation of at least two members of the pRb family is required to overcome p16-induced senescence in breast cancer cells. On the other hand, they showed that abrogation of pRb, but not of p107 and/ or p130, attenuates senescence in HMECs, suggesting a non-redundant critical role of pRb in HMEC senescence. These data are consistent with a recent report demonstrating that pRb has a non-redundant role in repressing DNA replication during H-ras-induced senescence of human fibroblasts,4 and explain why pRb, but not p107 or p130, is frequently mutated in cancer. Interestingly, although abrogation of pRb is critical for HMECs escaping senescence, simultaneous depletion of pRb together with either p107, p130 or both accelerates bypass of senescence. This suggests that p107 and p130 help pRb to trigger/maintain HMEC senescence in culture and possibly in vivo. Although each pRb family protein preferentially binds to different members of the E2F family,5 the contribution of each E2F family protein in escaping p16-mediated senescence remains unclear. Therefore, it will be interesting to see whether the critical role of pRb, and a supportive role of p130 and p107, in p16-mediated HMEC senescence depend on how each pRb family protein interacts with an E2F family protein.

Bazarov et al. also showed that even aggressive p53-negative breast cancer cells undergo cellular senescence upon ectopic p16 expression. These results are quite encouraging from an epigenetic therapy point of view. Silencing of p16 often occurs in breast cancer cells via promoter methylation. During DNA replication, cells require new p16 promoter methylation to keep p16 silenced. The observations of Bazarov et al. suggest that we may be able to stop the growth of even aggressive p53-negative breast cancers in patients by inducing p16 expression in cancer cells using DNA methylation inhibitors. Back to the question of running family business: “it appears that pRb is still the boss, but in some cases, it may get a helping hand from his cousins- p107 and p130.”


Previously published online:


1. Stampfer MR,et al. Cancer LettYear: 200319419920810.1016/S0304-3835(02)00707-312757978
2. Itahana K,et al. Mol Cell BiolYear: 20032338940110.1128/MCB.23.1.389-401.200312482990
3. Bazarov AV,et al. Cell CycleYear: 20121110081310.4161/cc.11.5.1949222333593
4. Chicas A,et al. Cancer CellYear: 2010173768710.1016/j.ccr.2010.01.02320385362
5. Classon M,et al. Nat Rev CancerYear: 20022910710.1038/nrc95012459729


[Figure ID: F1]

Figure 1. Contribution of pRb family proteins to p16-mediated senescence in breast cancer cells and HMECs. Knockdown of each of the three pRb family proteins in breast cancer cells does not abrogate ectopic p16-induced senescence, suggesting that either two of pRb family proteins can compensate for the loss of each pRb family proteins or all three of pRb family proteins play an additive role in p16-mediated senescence in breast cancer cells. On the other hand, knockdown of pRb, but not of p107 or p130, abrogates HMEC senescence, suggesting a non-redundant critical role for pRb in senescence of HMECs. However, the knockdown of either p107 or p130, in conjunction with pRb depletion, abrogates HMEC senescence more efficiently than pRb knockdown alone. This suggests a supporting role for p107 and p130 in maintaining HMEC senescence.

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