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Special Lecture |
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544
Preface
It was, indeed, a wonderful honor to receive the G. H. A. Clowes Memorial Award and present the Clowes Lecture at the Meeting for the American Association for Cancer Research. I have been fortunate to carry out research in the area of cancer biology at a remarkable time and to have had many truly extraordinary colleagues in this field. When I began my graduate student research in 1961, we did not truly understand the origins of cancer in humans, nor did we have the experimental tools to uncover the mutations or the genes involved in human cancer. Rather, we followed the advice of the exceptional individuals who were beginning the revolution in molecular biology; we chose simple experimental systems with the abiding faith that viruses that cause tumors in hamsters, mice, or chickens would surely teach us something about cancer in humans. For their guidance, advice, friendship, and the example they set for me, I will always be indebted to Harold S. Ginsberg, my thesis advisor, and Robert L. Sinsheimer, my postdoctoral advisor. I learned many lessons about science and life during my stay at the University of Pennsylvania and at the California Institute of Technology. Those were the years that prepared me for science at Princeton University and the exploration of the question: How does SV40 cause tumors in hamsters and transform cells in culture? Princeton in the 1970s was truly fertile ground. Arriving as assistant professors were Bruce Alberts, Mark Kirschner, Uli Laemmli, Harold Weintraub, Abe Worcel, and many others to join a senior faculty with very high standards and well-articulated expectations. It was my good fortune to be in the right place at the right time.
At about this junction, Peter Tegtmeyer had isolated a series of temperature-sensitive mutants of SV40 that blocked infectious virus production at the nonpermissive temperature. One group of these mutants, in complementation group A, failed to transform cells in culture (1)
, and even if the mutants were used to transform cells at the permissive temperature, they failed to maintain the "transformed phenotype" at the nonpermissive temperature (2
, 3)
. This had been shown previously with polyoma virus, with which tumors only formed in mouse tissues with low temperatures (4)
. The Tegtmeyer group (5)
went on to identify the group A protein as the SV40 large tumor (T) antigen. Animals bearing SV40-induced tumors express the tumor antigen in their cancer cells. The animals recognize this viral protein as foreign and produce antibodies to it. It was these antibodies that Tegtmeyer et al. (5)
used to immunoprecipitate the T-antigen and show it had a Mr of 
100,000 using Laemmli SDS gels.
As we repeated these experiments, it became clear that, in addition to the Mr 100,000 protein immunoprecipitated from SV40-infected or -transformed cells, a number of other proteins were "trapped" in the immunoprecipitate, which we commonly interpreted as proteolytic breakdown products of the viral T-antigen (and some of them were just that). Our first clue that there was more to this observation than that facile explanation came when a graduate student in my laboratory, Dan Linzer, used the antiserum from hamsters bearing SV40-induced tumors (a serum prepared in the laboratory by my technician Angie Teresky) to look for "tumor antigens" in cells not infected or transformed by SV40. Dan Linzer found such an antigen in murine testicular teratocarcinoma cells. A protein of Mr 53,008–54,000 from these cells comigrated in SDS gels with a protein in SV40-transformed cells. Although, I was skeptical and pointed out how many proteins of Mr 53,000 there must be in cells, Dan Linzer used peptide mapping to show that the p53 in SV40-transformed cells and in teratocarcinomas was a cellular protein recognized by SV40 tumor-bearing sera (6) . In fact, monoclonal antibodies directed against SV40 large T-antigen, coimmunoprecipitated this p53 protein so it was in a complex with SV40 large T-antigen (6) . This result was simultaneously reported by David Lane and Lionel Crawford (7) .
By 1982–1984, the first murine and then human cDNA clones of p53 were isolated. In my group, Moshe Oren (then a postdoctoral fellow) and Diane Pennica at Genentech played a central role in obtaining our clones (8 , 9) . After a 3–4-year confusion about who had wild-type p53 clones or mutant p53 clones, everyone agreed: the mutant p53 cDNA can transform cells in culture, and wild-type p53 cDNA clones actually prevent cellular transformation by a wide variety of oncogenes (10) . These hard-won facts surfaced from several years of work in my group by Cathy Finlay and Phil Hinds. Just as Bert Vogelstein’s group (11 , 12) reported that p53 mutations were found in both alleles of colon cancer cells, the experiments of Finlay, Hinds, and myself (13) showed that p53 was not an oncogene but a tumor suppressor gene.
From the discovery of p53 in 1979 until 1989, the hope that a simple virus that causes cancer in hamsters could shed light upon the origins of human cancer seemed to become a fair assumption. The years from 1989 to the present have shown just how central the p53 tumor suppressor gene is in human cancers. We now have the hope that we can understand how cancers arise and evolve and, in so doing, understand how to stop the growth of cancer cells.
Introduction
Since its discovery in 1979 as a cellular target of the transforming large T-antigen of SV40 (6 , 7) , the importance of the role of the p53 protein as a tumor suppressor has become increasingly clear. Both alleles of the p53 gene are mutated or deleted in a large percentage of a variety of both spontaneous and inherited human tumors (11 , 12 , 14, 15, 16) . In addition, deletion of the p53 gene from mice causes them to be highly predisposed to cancer (17) . In cell culture, functional p53 protein activity is often lost during the immortalization process (18) , and forced over-expression of p53 causes cells to undergo growth arrest (19, 20, 21) or apoptosis (22, 23, 24, 25, 26) . These data amply demonstrate that p53 activity is incompatible with excessive cell growth.
The function of p53 in regulating the growth and division of cells commonly occurs in response to DNA damage (27, 28, 29) . The mechanisms by which p53 controls the fate of cells that encounter DNA damage are not fully understood, but several steps of its pathway have been ascertained. First, p53 protein levels rise after DNA damage because p53 is stabilized by a posttranslational mechanism (30) . It then functions as a transcription factor, activating the expression of several genes, not all of which have been identified to date. Some of the genes induced by p53 include: p21waf1, which contributes to growth arrest; Bax, which induces apoptosis; GADD45, which functions in DNA repair; and cyclin G, the function of which is not yet known (31, 32, 33, 34) . In addition, p53 may have transcription-independent activities, possibly by direct signaling through its proline domain (35) , that contribute to its growth arrest and apoptotic activities after DNA damage. By preventing the further division of cells that have encountered genetic insult, p53 checks the uncontrolled growth of cells sustaining oncogenic mutations, thus directly protecting the organism from cancer.
A major step toward understanding the p53 pathway came with the identification of the Mdm2 oncogene (36 , 37) . It was soon determined not only that Mdm2 is transcriptionally induced by p53 after its stabilization by DNA damage (38, 39, 40, 41) but also that MDM2 binds to p53 and blocks its ability to function as a transcription factor and tumor suppressor (42, 43, 44, 45, 46) . MDM2 functions in this capacity by directly blocking p53’s activity as a transcription factor (47, 48, 49) and by targeting it for degradation (50 , 51) . This inhibition of p53 by MDM2 can clearly be observed in mice. Homologous deletion of Mdm2 is lethal at very early stages of embryogenesis but is completely rescued by the additional deletion of the p53 gene. This result demonstrates that the inhibition of p53 by MDM2 is essential for life at an early developmental stage (52 , 53) . MDM2 and p53 are, therefore, predicted to form an autoregulatory feedback loop in which p53 limits its own activity through the production of MDM2.
Because the p53 protein becomes stabilized and active as a transcription factor following DNA damage, it is apparent that the inhibition of p53 by MDM2 can be regulated to modulate p53 activity and break the MDM2-p53 autoregulatory feedback loop. This Clowes Memorial Award lecture will discuss recent evidence that supports these ideas: i.e., cell lines that overexpress MDM2 exhibit a significant p53 response after DNA damage, despite the presence of large amounts of its negative regulator, MDM2. Current knowledge of the mechanistic details of MDM2’s inhibition of p53 are then reviewed, to shed light on how MDM2’s inhibition of p53 can be overcome either by the cell in response to DNA damage or by experimental design in an attempt to activate p53 as a potential cancer therapy.
The p53 Protein Can Overcome Inhibition by MDM2
Among tumors that retain two wild-type alleles of p53, many overexpress the MDM2 oncoprotein (54, 55, 56, 57, 58, 59, 60, 61)
. Through an examination of cell lines derived from such tumors (Table 1)
, the effect of MDM2 overexpression on the response of p53 to DNA damage can be determined.
|
, top row). No p53 protein was detected in the p53-null H1299 lung carcinoma cell line after UV irradiation as expected (the p53 gene is deleted). After a similar time course of treatment with 10 µM etoposide, the levels of p53 protein increased at least 2-fold, 3-fold, and 8-fold, respectively in the same cell lines (Fig. 1
, top row). These results indicate that the 20–100-fold overexpressed MDM2 protein in these cells is unable to degrade p53 and prevent the observed increase in p53 levels after DNA damage.
|
. Because the different cell lines have approximately equal levels of p53 protein after DNA damage, there appears to be a complete inhibition of MDM2’s ability to degrade p53 after DNA damage, which allows for a substantial increase in p53 levels (Fig. 1)
.
As well as targeting p53 for degradation, MDM2 also binds to p53 in the nucleus and prevents its ability to activate transcription (45
, 49)
. To determine whether this activity of MDM2 is, like its ability to degrade p53, inhibited after DNA damage, the levels of p53-responsive proteins were observed by Western blot analysis in the same cell lines described above. The level of the MDM2 protein, whose gene is responsive to p53 (38
, 39)
, was observed in the same lysates (Fig. 1
, second row). After UV irradiation, MDM2 protein levels fall (in a p53-independent manner), as observed at early time points in Fig. 1
and as has been reported previously (64)
. At later times after UV irradiation, MDM2 levels increase in each of the cell lines that contain wild-type p53 but not in the p53-null H1299 cell line. A similar, p53-independent (transcriptional) increase in MDM2 levels was observed in these same cells after etoposide treatment. In addition, the levels of p21waf1, the product of another p53-responsive gene (31)
, rose after both of these DNA-damaging treatments in a p53-dependent manner (Figure 1
, third row). The levels of the small GTP-binding protein ran, which is not responsive to p53, was determined from the same lysates as a control, and did not change upon DNA damage (Figure 1
, last row). These observations clearly demonstrate that the p53 protein is not only stabilized after DNA damage but is also active as a transcription factor in cell lines that contain high levels of its negative regulator, MDM2. This result demonstrates that the p53-MDM2 autoregulatory feedback loop is modulated in response to DNA damage to allow for the appropriate p53 responses. Some cellular activity, therefore, regulates the p53-MDM2 feedback loop.
To discern how the cell allows for the inhibition of MDM2’s regulation of p53 after DNA damage, an understanding of the details of this regulation is required. In the past several years, a great deal has been learned about the mechanisms by which MDM2 inhibits p53’s activities.
The Mechanisms of MDM2’s Inhibition of p53
The NH2-terminal domain of MDM2 forms a deep cleft lined with hydrophobic and aromatic amino acids that interact directly with an amphipathic 
-helix formed by the NH2 terminus of the p53 protein (42
, 65
, 66)
. Through this interaction, MDM2 inhibits the transcriptional activation of p53 both in cotransfection experiments and in an in vitro transcription assay (43, 44, 45
, 49)
. This inhibition of p53 transcriptional activity by MDM2 is thought to result from the blocking of the transactivation domain of p53 (47
, 67)
. MDM2 binds to the same amino acids that p53 uses to contact TAFII31 and TAFII70 and activate transcription (47
, 48
, 67)
, suggesting that MDM2 competes with the transcription factor IID transcription factor complex for p53 interaction and, thereby, blocks its ability to activate transcription.
MDM2’s interaction with p53 can also result in the degradation of the p53 protein (50
, 51)
. A recently identified activity of MDM2, that of nuclear-cytoplasmic shuttling, is required for the degradation of p53 by MDM2 and has shed light on the mechanism of this p53 degradation pathway (68
, 69)
. A conserved, leucine-rich sequence in MDM2 resembles a NES3
sequence from several proteins that are exported from the nucleus into the cytoplasm (Refs. 70, 71, 72, 73, 74
; Fig. 2A
). MDM2’s ability to shuttle between the nuclear and cytoplasmic compartments of the cell as mediated by its NES and NLS sequences can be observed using heterokaryon assays (68)
. When human cells are transfected with a human MDM2 expression plasmid and subsequently fused to untransfected murine cells in the presence of cycloheximide, the human MDM2 protein can be detected in both the human and murine nuclei of heterokaryons (Ref. 68
; Fig. 2B
, top). This localization pattern occurs as the exogenous MDM2 protein is exported from the human nucleus, in which it is originally located, via its NES to the cytoplasm and then into the murine nucleus using its NLS. The nuclear export of MDM2 is dependent on its NES sequence, as mutations in this sequence (see Fig. 2 A
) prevent the export of the exogenous MDM2 from the human nucleus in this assay (Ref. 68
; Fig. 2B
, bottom).
|
The impact of MDM2’s ability to shuttle between the nucleus and cytoplasm in the regulation of p53 was subsequently studied. The nuclear export of MDM2 has a rather complicated effect upon the ability of p53 to activate the transcription of a reporter gene during transfection assays. When relatively low levels of p53 were present, MDM2 with a mutated NES (which is retained in the nucleus; Fig. 2
) was a better inhibitor of p53 activity than was wild-type MDM2. This observation is likely a result of MDM2’s direct block of p53’s interaction with the transcription machinery in the cell nucleus (68)
. However, when p53 was present at higher levels, the mutant NES form of MDM2 was a less efficient inhibitor of p53 activity than wild-type MDM2 (68)
. This result was likely due to: (a) an excess of p53, the transcription activity of which could not be blocked by MDM2 (this requires a 1:1 stoichiometric ratio of p53 to MDM2); and (b) an inability of MDM2 to target p53 for degradation when it lacked nuclear export ability.
To determine whether the nuclear export of MDM2 is, in fact, required for the degradation of p53, p53 protein levels were determined after its expression alone or with either wild-type or the NES-mutant form of MDM2 in the p53-null Saos-2 cells. Equivalent levels of the two forms of MDM2 were expressed during the experiment (Fig. 3)
. Coexpression of p53 and wild-type MDM2 led to a sharp decrease in the levels of p53 protein compared to the levels of p53 in the absence of MDM2 (Ref. 68
; Fig. 3
). However, when the mutant-NES form of MDM2 was coexpressed with p53 in these cells, the levels of the protein were unaffected (Fig. 3)
. The proteasome inhibitor MG132 blocked the reduction in p53 levels observed in the presence of wild-type MDM2. This last result suggests that the decrease in p53 levels by MDM2 is due to proteasomal degradation in the cytoplasm, consistent with previous results (50
, 51)
. Additional support for the assertion that nuclear export of MDM2 is required for the degradation of p53 is that expression of the nuclear export inhibitor fusion protein, NLS-rex, inhibits MDM2’s nuclear export and also blocks the degradation of p53 by MDM2 (68)
.
|
Consistent with the model in which MDM2 mediates the steady-state levels of p53 by shuttling it from the nucleus for degradation by cytoplasmic proteasomes, the addition of 5 ng/ml LMB to a variety of cell lines containing wild-type (SJSA and the MCF-7 breast carcinoma cell line) or mutant (Sk-mel-2 melanoma cell line) p53 led to a marked increase in the steady-state levels of the p53 protein (Ref. 69
; Fig. 4 A
). Subsequent p53-dependent increases in MDM2 and p21waf1 protein levels were also observed in these cells (Fig. 4A)
, suggesting that the p53 produced was functional and was located in the nucleus. This result was confirmed by immunofluorescent studies and substantiates the concepts developed here (69)
.
|
1 h to almost 4 h (Ref. 69
; Fig. 4B
). These results support the validity of the model in which MDM2 and p53 first interact in the nucleus and then shuttle to the cytoplasm, where p53 is then targeted to cytoplasmic proteasomes for degradation. The Regulation of MDM2’s Inhibition of p53
Thus two mechanisms combine to regulate p53 activity or levels using MDM2: (a) competition for p53 binding to the TAFs and (b) shuttling p53 from the nucleus to the cytoplasm for proteasome degradation. This then provides the cell with several places to block the inhibition of p53 by MDM2 after DNA damage (Fig. 5)
. For instance, blocking the formation of MDM2-p53 complexes would prevent both of these events. In fact, blocking complex formation by the microinjection of monoclonal antibodies to MDM2 or by transfection of a plasmid expressing a competing, p53-like peptide leads to an increase in p53-dependent transcriptional activity (78
, 79)
. Recent evidence demonstrates that a block in the formation of the MDM2-p53 complex can occur in cells by a phosphorylation event at one or two serine residues located in the NH2 terminus of p53, which is observed after DNA damage (80)
.
|
).
Finally, nuclear export of MDM2, as a requirement for MDM2’s degradation of p53, presents another potential step for regulation. The addition of the nuclear export inhibitor, LMB, does, in fact, stabilize the p53 protein and increase p53-dependent transcriptional activation (Ref. 69
; Fig. 4
). Whether or not cells block nuclear export by MDM2 as an additional layer of control over the inhibition of p53 remains to be determined.
Conclusions and Prospectives
The experiments presented and reviewed here have led to the model presented in Fig. 5
. In a normal cell, low levels of inactive p53 proteins are maintained by the MDM2 protein, which blocks p53 transcriptional activity in the nucleus and shuttles p53 into the cytoplasm to be degraded by the cytoplasmic proteasome. In response to many types of DNA damage, p53 protein levels rise and p53 activities become functional. DNA damage is detected by a diverse set of repair activities that are specific for the type of DNA damage and that signal to the p53 protein that a specific type of DNA damage has occurred (Table 2)
. After 
irradiation, the ATM protein kinase appears to phosphorylate the p53 protein at Ser-15 and Ser-31 residues, which, in turn, blocks p53 from binding to MDM2. These events result in increased p53 activities and levels. After UV irradiation, the MDM2 protein is degraded and MDM2 mRNA levels fall (55)
. In addition, Ser-392 (at the p53 COOH terminus) of p53 is phosphorylated (82)
, probably by the cyclin H-CDK7 protein kinase, which is part of the nucleotide excision repair complex. Phosphorylation of Ser-392 activates p53 for binding to specific DNA sequences, a prelude to transcriptional activation (83
, 84)
. This same enzyme also phosphorylates the NH2 terminus of p53 (85)
, blocking p53-MDM2 interactions and stabilizing p53. DNA containing apurinic acid sites are repaired by the apurinic acid sites nuclease, Ref-1, which can regulate the redox potential of p53. This event, in turn, activates p53 for transcription (86)
. There remain several other possible ways to regulate p53 activities. The histone acetyl-transferases such as the p300 coactivator, acetylate the COOH-terminal lysines of p53 activating it for specific DNA binding (87
, 88)
. A block in the ability of MDM2 to shuttle into the cytoplasm, as shown here, will result in activation of p53 (69)
. This implies that regulation of the CRM1-RanGTP shuttling pathway could well result in p53 activation (Fig. 5
, step B).
|
, A
B
C
via step B), very little is known about the reversal of this process (Fig. 5
, C
B
A
via step D). MDM2 levels increase in a p53-dependent fashion forming an autoregulatory loop that acts in a sinusoidal fashion. The interruption of this process favoring different states (A or C) is fertile ground for future research. Indeed, little is known about the regulation of MDM2 protein stability or Mdm2 gene transcription, but clearly, both play a role in p53 activation and inhibition. In recent years, there have been rather clear suggestions that the MDM2 protein may have p53-independent functions that are related to cell division and the cancer phenotype. Elucidation of these functions will surely open new pathways of understanding cancer biology. The regulation of MDM2 mediated p53 activity by p19Arf (89 , 90) has begun to connect the role of p53 back to a broader spectrum of mutations in the cancer cell. This is clearly an area of research that will open new insights into the cellular regulatory pathways that are defective in cancer cells.
Finally, agents that activate p53 in cancer cells all have the potential to selectively kill these cells. Whether this relies upon breaking p53-MDM2 complexes (78 , 79) , reactivating inactive forms of wild-type p53 in a cell (91) , or even introducing a wild-type p53 gene into a cancer cell (92) , these approaches are the beginning of a rational basis for therapy. It is clear that p53-mediated apoptosis is modulated by activated oncogene products not found in normal cells (23, 24, 25) . It is this fundamental observation that could lead us to drugs or agents with true selective toxicity for tumor cells (expressing activated oncogene products) over normal cells. The generation of such selective drugs must be our clearest goal.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Presented by Dr. Arnold J. Levine at the 89th Annual Meeting of the American Association for Cancer Research, March 29, 1998, New Orleans, LA. 
2 To whom requests for reprints should be addressed. Present address: The Rockefeller University, 1230 York Avenue, New York, NY 10021-6399.
3 The abbreviations used are: NES, nuclear export signal; NLS, nuclear localization signal; LMB, leptomycin B.
Received 10/23/98. Accepted 10/30/98.
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F. Mancini, F. Gentiletti, M. D'Angelo, S. Giglio, S. Nanni, C. D'Angelo, A. Farsetti, G. Citro, A. Sacchi, A. Pontecorvi, et al. MDM4 (MDMX) Overexpression Enhances Stabilization of Stress-induced p53 and Promotes Apoptosis J. Biol. Chem., February 27, 2004; 279(9): 8169 - 8180. [Abstract] [Full Text] [PDF]
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C. D. Knights, Y. Liu, E. Appella, and M. Kulesz-Martin Defective p53 Post-translational Modification Required for Wild Type p53 Inactivation in Malignant Epithelial Cells with mdm2 Gene Amplification J. Biol. Chem., December 26, 2003; 278(52): 52890 - 52900. [Abstract] [Full Text] [PDF]
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 G. Ganguli and B. Wasylyk p53-Independent Functions of MDM2 Mol. Cancer Res., December 1, 2003; 1(14): 1027 - 1035. [Abstract] [Full Text] [PDF]
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 L. Rosano, F. Spinella, V. Di Castro, M. R. Nicotra, A. Albini, P. G. Natali, and A. Bagnato Endothelin Receptor Blockade Inhibits Molecular Effectors of Kaposi's Sarcoma Cell Invasion and Tumor Growth in Vivo Am. J. Pathol., August 1, 2003; 163(2): 753 - 762. [Abstract] [Full Text] [PDF]
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P. Wang, H. Gao, Y. Ni, B. Wang, Y. Wu, L. Ji, L. Qin, L. Ma, and G. Pei beta -Arrestin 2 Functions as a G-Protein-coupled Receptor-activated Regulator of Oncoprotein Mdm2 J. Biol. Chem., February 14, 2003; 278(8): 6363 - 6370. [Abstract] [Full Text] [PDF]
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A. Bagnato, A. Cirilli, D. Salani, P. Simeone, A. Muller, M. R. Nicotra, P. G. Natali, and A. Venuti Growth Inhibition of Cervix Carcinoma Cells in Vivo by Endothelin A Receptor Blockade Cancer Res., November 15, 2002; 62(22): 6381 - 6384. [Abstract] [Full Text] [PDF]
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S. Vanzulli, A. Efeyan, F. Benavides, L. A. Helguero, G. Peters, J. Shen, C. J. Conti, C. Lanari, and A. Molinolo p21, p27 and p53 in estrogen and antiprogestin-induced tumor regression of experimental mouse mammary ductal carcinomas Carcinogenesis, May 1, 2002; 23(5): 749 - 758. [Abstract] [Full Text] [PDF]
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 D. Del Bufalo, V. Di Castro, A. Biroccio, M. Varmi, D. Salani, L. Rosano, D. Trisciuoglio, F. Spinella, and A. Bagnato Endothelin-1 Protects Ovarian Carcinoma Cells against Paclitaxel-Induced Apoptosis: Requirement for Akt Activation Mol. Pharmacol., March 1, 2002; 61(3): 524 - 532. [Abstract] [Full Text] [PDF]
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 D. Tolbert, X. Lu, C. Yin, M. Tantama, and T. Van Dyke p19ARF Is Dispensable for Oncogenic Stress-Induced p53-Mediated Apoptosis and Tumor Suppression In Vivo Mol. Cell. Biol., January 1, 2002; 22(1): 370 - 377. [Abstract] [Full Text] [PDF]
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L. Rosano, M. Varmi, D. Salani, V. Di Castro, F. Spinella, P. Giorgio Natali, and A. Bagnato Endothelin-1 Induces Tumor Proteinase Activation and Invasiveness of Ovarian Carcinoma Cells Cancer Res., November 1, 2001; 61(22): 8340 - 8346. [Abstract] [Full Text] [PDF]
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H. Wang, L. Nan, D. Yu, S. Agrawal, and R. Zhang Antisense Anti-MDM2 Oligonucleotides As a Novel Therapeutic Approach to Human Breast Cancer: In Vitro and in Vivo Activities and Mechanisms Clin. Cancer Res., November 1, 2001; 7(11): 3613 - 3624. [Abstract] [Full Text] [PDF]
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S. Wang and X. Shi Mechanisms of Cr(VI)-induced p53 activation: the role of phosphorylation, mdm2 and ERK Carcinogenesis, May 1, 2001; 22(5): 757 - 762. [Abstract] [Full Text] [PDF]
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 R. Maya, M. Balass, S.-T. Kim, D. Shkedy, J.-F. M. Leal, O. Shifman, M. Moas, T. Buschmann, Z.'e. Ronai, Y. Shiloh, et al. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage Genes & Dev., May 1, 2001; 15(9): 1067 - 1077. [Abstract] [Full Text]
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A. Bagnato, L. Rosano, V. Di Castro, A. Albini, D. Salani, M. Varmi, M. R. Nicotra, and P. G. Natali Endothelin Receptor Blockade Inhibits Proliferation of Kaposi's Sarcoma Cells Am. J. Pathol., March 1, 2001; 158(3): 841 - 847. [Abstract] [Full Text] [PDF]
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L. Li, J. Liao, J. Ruland, T. W. Mak, and S. N. Cohen A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control PNAS, February 13, 2001; 98(4): 1619 - 1624. [Abstract] [Full Text] [PDF]
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 D Negorev, A. Ishov, and G. Maul Evidence for separate ND10-binding and homo-oligomerization domains of Sp100 J. Cell Sci., January 1, 2001; 114(1): 59 - 68. [Abstract] [PDF]
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D. R. Morris and A. P. Geballe Upstream Open Reading Frames as Regulators of mRNA Translation Mol. Cell. Biol., December 1, 2000; 20(23): 8635 - 8642. [Full Text]
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D. Salani, V. Di Castro, M. R. Nicotra, L. Rosano, R. Tecce, A. Venuti, P. G. Natali, and A. Bagnato Role of Endothelin-1 in Neovascularization of Ovarian Carcinoma Am. J. Pathol., November 1, 2000; 157(5): 1537 - 1547. [Abstract] [Full Text] [PDF]
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D. Salani, G. Taraboletti, L. Rosano, V. Di Castro, P. Borsotti, R. Giavazzi, and A. Bagnato Endothelin-1 Induces an Angiogenic Phenotype in Cultured Endothelial Cells and Stimulates Neovascularization In Vivo Am. J. Pathol., November 1, 2000; 157(5): 1703 - 1711. [Abstract] [Full Text] [PDF]
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 A. Di Bacco, K. Keeshan, S. L. McKenna, and T. G. Cotter Molecular Abnormalities in Chronic Myeloid Leukemia: Deregulation of Cell Growth and Apoptosis Oncologist, October 1, 2000; 5(5): 405 - 415. [Abstract] [Full Text]
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R. J. Sleiman and B. W. Stewart Early Caspase Activation in Leukemic Cells Subject to Etoposide-induced G2-M Arrest: Evidence of Commitment to Apoptosis Rather Than Mitotic Cell Death Clin. Cancer Res., September 1, 2000; 6(9): 3756 - 3765. [Abstract] [Full Text]
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 N. Mailand, J. Falck, C. Lukas, R. G. Syljuåsen, M. Welcker, J. Bartek, and J. Lukas Rapid Destruction of Human Cdc25A in Response to DNA Damage Science, May 26, 2000; 288(5470): 1425 - 1429. [Abstract] [Full Text]
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 C.-T. Yang, L. You, C.-C. Yeh, J. W.-C. Chang, F. Zhang, F. McCormick, and D. M. Jablons Adenovirus-Mediated p14ARF Gene Transfer in Human Mesothelioma Cells J Natl Cancer Inst, April 19, 2000; 92(8): 636 - 641. [Abstract] [Full Text] [PDF]
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J. S. Butel Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease Carcinogenesis, March 1, 2000; 21(3): 405 - 426. [Abstract] [Full Text] [PDF]
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G. Xiao, A. Chicas, M. Olivier, Y. Taya, S. Tyagi, F. R. Kramer, and J. Bargonetti A DNA Damage Signal Is Required for p53 to Activate gadd45 Cancer Res., March 1, 2000; 60(6): 1711 - 1719. [Abstract] [Full Text]
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D. A. Sharp, S. A. Kratowicz, M. J. Sank, and D. L. George Stabilization of the MDM2 Oncoprotein by Interaction with the Structurally Related MDMX Protein J. Biol. Chem., December 31, 1999; 274(53): 38189 - 38196. [Abstract] [Full Text] [PDF]
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R. Alarcon, C. Koumenis, R. K. Geyer, C. G. Maki, and A. J. Giaccia Hypoxia Induces p53 Accumulation through MDM2 Down-Regulation and Inhibition of E6-mediated Degradation Cancer Res., December 1, 1999; 59(24): 6046 - 6051. [Abstract] [Full Text] [PDF]
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 K. W. Kohn Molecular Interaction Map of the Mammalian Cell Cycle Control and DNA Repair Systems Mol. Biol. Cell, August 1, 1999; 10(8): 2703 - 2734. [Abstract] [Full Text]
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