Loss of p21 disrupts p14 ARF-induced G1 cell cycle arrest but augments p14 ARF-induced apoptosis in human carcinoma cells
Authors: Dilek Güner
Jana Wendt
Anne Hasenjäger
Berlinda Verdoodt
Guillaume Normand
Philipp G Hemmati
Bernd Dörken
Clarissa von Haefen
Peter T Daniel
Journal: Oncogene (2005)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: INK4a locus; tumor suppressor proteins; p16 INK4a; p14 ARF; p53
Affiliations: Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Berlin-Buch, Germany.

Abstract:  The human INK4a locus encodes two structurally unrelated tumor suppressor proteins, p16 INK4a and p14 ARF (p19 ARF in the mouse), which are frequently inactivated in human cancer. Both the proapoptotic and cell cycle-regulatory functions of p14 ARF were initially proposed to be strictly dependent on a functional p53/mdm-2 tumor suppressor pathway. However, a number of recent reports have implicated p53-independent mechanisms in the regulation of cell cycle arrest and apoptosis induction by p14 ARF. Here, we show that the G1 cell cycle arrest induced by p14 ARF entirely depends on both p53 and p21 in human HCT116 and DU145 carcinoma cells. In contrast, neither loss of p53 nor p21 impaired apoptosis induction by p14 ARF as evidenced by nuclear DNA fragmentation, phosphatidyl serine exposure, and caspase activation, which included caspase-3/7- and caspase-9-like activities. However, lack of functional p21 resulted in the accumulation of cells in G2/M phase of the cell cycle and markedly enhanced p14 ARF-induced apoptosis that was, nevertheless, efficiently inhibited by the cell permeable broad-spectrum caspase inhibitor zVAD-fmk (valyl-alanyl-aspartyl-(O)-methyl)-fluoromethylketone). Thus, loss of cell cycle restriction point control in the absence of p21 may interfere with p14 ARF-induced apoptosis. Finally, these data indicate that the signaling events required for G1 cell cycle arrest and apoptosis induction by p14 ARF dissociate upstream of p53. 

Retracted: No

PubPeer comments:
 Figure 1. Image duplication. ![file] , 
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 Dear Dr. Eumenopis, Thank you very much for your comments on our article related to possible duplicated images. I am the first author of this paper and with the permission from the senior authors Dr. Zhu and Dr. Shen, I prepare the following response to your inquiry. We have carefully checked the manuscript and the raw data immediately upon receiving your comment, and found that the mentioned images have indeed been misplaced in Figure 1 and Figure 4a. We sincerely apologize for our mistakes in the image preparation and we have would like to replace these with the original correct images as detailed below. 1. In Figure 1, CD68 immunostaining in MI tissues from KO (day 3) was careless mixture with MI tissues from KO (day 8). Since all the IHC data in Figure 1 was processing at the same time, IHC layer of MI tissues from KO mice (day 3) was unintentionally confused with the original layer in MI tissues from KO mice (day 8) during images processing, resulting in unconscious deletion of the real layer in MI tissues from KO mice (day 8). We have corrected it and provided the original photos. We immediately submitted a correction, and other repeat photos in group of MI tissues from KO mice (day 8) to the editorial office. On a positive note, it was not contradictory to our finding that the NaHS rescued the decrease of infiltrating macrophages caused by CSE depletion, and promoted macrophage infiltration in the early of MI. Erratum Figure 1: ![file] 2. In Figure 4a, the transwell image of PF573228+NaHS was overlapped by the NSC23766+NaHS group. During the processing of transwell images, PF573228+NaHS group was unintentionally confused with NSC23766+NaHS group, making them mixed with each other in the layers processing of all the images in Figure 4a. Herein, we have corrected image of PF573228+NaHS and provided the original photos. We immediately submitted a correction and another set of migration ability to verify the effect of PF573228 during NaHS treatment to the editorial office. On a positive note, statistical analysis in Figure 4a is unchanged, which also confirm that the migration of RAW264.7 cells accelerated by NaHS were inhibited by PF573228. Erratum Figure 4a: ![file] Thank you again for your interests in our works. After received your comments and realized our mistakes, we immediately contacted the editorial office to inquiry about the process to make the necessary corrections by issuing a corrigendum. We will do our best to review all current work and publication process bysetting up a new protocol for image processing to minimize the impact of these errors and prevent it from happening again. Sincerely, Lei Miao, Ph.D E-mail: miaoleimolly@126.com ,