Identification of GRO1 as a Critical Determinant for Mutant p53 Gain of Function

Mutant p53 gain of function contributes to cancer progression, increased invasion and metastasis potentials, and resistance to anticancer therapy. The ability of mutant p53 to acquire its gain of function is shown to correlate with increased expression of progrowth genes, such as c-MYC, MDR1, and NF-κB2. However, most of the published studies to identify mutant p53 target genes were performed in a cell system that artificially overexpresses mutant p53. Thus, it remains unclear whether such mutant p53 targets can be regulated by endogenous physiological levels of mutant p53. Here, we utilized SW480 and MIA-PaCa-2 cells, in which endogenous mutant p53 can be inducibly knocked down, to identify mutant p53 target genes that potentially mediate mutant p53 gain of function. We found that knockdown of mutant p53 inhibits GRO1 expression, whereas ectopic expression of mutant R175H in p53-null HCT116 cells increases GRO1 expression. In addition, we found that endogenous mutant p53 is capable of binding to and activating the GRO1 promoter. Interestingly, ectopic expression of GRO1 can rescue the proliferative defect in SW480 and MIA-PaCa-2 cells induced by knockdown of mutant p53. Conversely, knockdown of endogenous GRO1 inhibits cell proliferation and thus abrogates mutant p53 gain of function in SW480 cells. Taken together, our findings define a novel mechanism by which mutant p53 acquires its gain of function via transactivating the GRO1 gene in cancer cells. Thus, targeting GRO1 for cancer therapy would be applicable to a large portion of human tumors with mutant p53, but the exploration of GRO1 as a potential target should take the mutation status of p53 into consideration. Mutant p53 gain of function contributes to cancer progression, increased invasion and metastasis potentials, and resistance to anticancer therapy. The ability of mutant p53 to acquire its gain of function is shown to correlate with increased expression of progrowth genes, such as c-MYC, MDR1, and NF-κB2. However, most of the published studies to identify mutant p53 target genes were performed in a cell system that artificially overexpresses mutant p53. Thus, it remains unclear whether such mutant p53 targets can be regulated by endogenous physiological levels of mutant p53. Here, we utilized SW480 and MIA-PaCa-2 cells, in which endogenous mutant p53 can be inducibly knocked down, to identify mutant p53 target genes that potentially mediate mutant p53 gain of function. We found that knockdown of mutant p53 inhibits GRO1 expression, whereas ectopic expression of mutant R175H in p53-null HCT116 cells increases GRO1 expression. In addition, we found that endogenous mutant p53 is capable of binding to and activating the GRO1 promoter. Interestingly, ectopic expression of GRO1 can rescue the proliferative defect in SW480 and MIA-PaCa-2 cells induced by knockdown of mutant p53. Conversely, knockdown of endogenous GRO1 inhibits cell proliferation and thus abrogates mutant p53 gain of function in SW480 cells. Taken together, our findings define a novel mechanism by which mutant p53 acquires its gain of function via transactivating the GRO1 gene in cancer cells. Thus, targeting GRO1 for cancer therapy would be applicable to a large portion of human tumors with mutant p53, but the exploration of GRO1 as a potential target should take the mutation status of p53 into consideration. It is known that mutation of p53 and/or inactivation of the p53 pathway are a hallmark of ∼50% human tumors. p53 is a tumor suppressor, and mutation of p53 leads to loss of its tumor-suppressing functions. Furthermore, a growing number of studies have provided compelling evidence that some p53 mutants have acquired additional functions that promote cancer development and progression, called gain-of-function (1Kalo E. Buganim Y. Shapira K.E. Besserglick H. Goldfinger N. Weisz L. Stambolsky P. Henis Y.I. Rotter V. Mol. Cell. Biol. 2007; 27: 8228-8242Crossref PubMed Scopus (61) Google Scholar, 2Bossi G. Lapi E. Strano S. Rinaldo C. Blandino G. Sacchi A. Oncogene. 2006; 25: 304-309Crossref PubMed Scopus (174) Google Scholar). Accordingly, gain of function was found to include the ability of mutant p53 to modulate specific target genes, such as MDR1 and c-MYC (3Atema A. Chene P. Cancer Lett. 2002; 185: 103-109Crossref PubMed Scopus (11) Google Scholar, 4Frazier M.W. He X. Wang J. Gu Z. Cleveland J.L. Zambetti G.P. Mol. Cell. Biol. 1998; 18: 3735-3743Crossref PubMed Scopus (176) Google Scholar), which mediate tumor cells to acquire various tumorigenic properties. However, most of the published studies to identify mutant p53 target genes were performed in a cell system that artificially overexpresses exogenous mutant p53 proteins. Thus, it remains unclear whether these mutant p53 targets can be regulated by endogenous physiological levels of mutant p53. Growth-regulated oncogene 1 (GRO1 or CXCL1) is found as an inflammatory factor and necessary for wound healing by modulating cell migration and angiogenesis (5Lane B.R. Liu J. Bock P.J. Schols D. Coffey M.J. Strieter R.M. Polverini P.J. Markovitz D.M. J. Virol. 2002; 76: 11570-11583Crossref PubMed Scopus (74) Google Scholar, 6Rennekampff H.O. Hansbrough J.F. Woods Jr., V. Dore C. Kiessig V. Schroder J.M. Arch. Dermatol. Res. 1997; 289: 204-212Crossref PubMed Scopus (34) Google Scholar). GRO1, a 73-amino acid secreted protein, contains a 3-amino acid motif (ELR; glutamate, leucine, and arginine) between the N terminus and the first cysteine (7Bechara C. Chai H. Lin P.H. Yao Q. Chen C. Med. Sci. Monit. 2007; 13: RA87-RA90PubMed Google Scholar). GRO1 is structurally and functionally related to GRO2 (CXCL2), GRO3 (CXCL3), and interleukin-8. These four ligands constitute the CXC chemokine subfamily. All four ligands bind to the seven-transmembrane G-protein-coupled receptor CXCR2, with GRO1 having the highest affinity (8Hammond M.E. Shyamala V. Siani M.A. Gallegos C.A. Feucht P.H. Abbott J. Lapointe G.R. Moghadam M. Khoja H. Zakel J. Tekamp-Olson P. J. Biol. Chem. 1996; 271: 8228-8235Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Upon ligand-receptor interaction, various signaling cascades are activated, including ERK1/2, JAK2-STAT3, phosphatidylinositol 3-kinase, and tyrosine kinases, to promote cell proliferation, angiogenesis, and cell invasion and migration (9Wang B. Hendricks D.T. Wamunyokoli F. Parker M.I. Cancer Res. 2006; 66: 3071-3077Crossref PubMed Scopus (156) Google Scholar, 10Burger M. Hartmann T. Burger J.A. Schraufstatter I. Oncogene. 2005; 24: 2067-2075Crossref PubMed Scopus (87) Google Scholar, 11Dhawan P. Richmond A. J. Leukocyte Biol. 2002; 72: 9-18PubMed Google Scholar). GRO1 is also found to be an oncogene and has pleiotropic effects on cell proliferation, tumor angiogenesis, invasion, and metastasis (9Wang B. Hendricks D.T. Wamunyokoli F. Parker M.I. Cancer Res. 2006; 66: 3071-3077Crossref PubMed Scopus (156) Google Scholar, 12Warner K.A. Miyazawa M. Cordeiro M.M. Love W.J. Pinsky M.S. Neiva K.G. Spalding A.C. Nor J.E. Neoplasia. 2008; 10: 131-139Crossref PubMed Scopus (61) Google Scholar). GRO1 is frequently overexpressed in many cancers, such as squamous cell carcinoma (12Warner K.A. Miyazawa M. Cordeiro M.M. Love W.J. Pinsky M.S. Neiva K.G. Spalding A.C. Nor J.E. Neoplasia. 2008; 10: 131-139Crossref PubMed Scopus (61) Google Scholar), breast cancer (13Bachmeier B.E. Mohrenz I.V. Mirisola V. Schleicher E. Romeo F. Hohneke C. Jochum M. Nerlich A.G. Pfeffer U. Carcinogenesis. 2008; 29: 779-789Crossref PubMed Scopus (181) Google Scholar), ovarian cancer (14Yang S. Lim M. Pham L.K. Kendall S.E. Reddi A.H. Altieri D.C. Roy-Burman P. Cancer Res. 2006; 66: 4285-4290Crossref PubMed Scopus (50) Google Scholar), colorectal cancer (15Wang D. Wang H. Brown J. Daikoku T. Ning W. Shi Q. Richmond A. Strieter R. Dey S.K. DuBois R.N. J. Exp. Med. 2006; 203: 941-951Crossref PubMed Scopus (299) Google Scholar), and prostate cancer (16Engl T. Relja B. Blumenberg C. Muller I. Ringel E.M. Beecken W.D. Jonas D. Blaheta R.A. Life Sci. 2006; 78: 1784-1793Crossref PubMed Scopus (76) Google Scholar). Consistent with this, ectopic expression of GRO1 promotes low GRO1-producing cells to proliferate and spontaneous metastasis in BALB/c mice (17Loukinova E. Dong G. Enamorado-Ayalya I. Thomas G.R. Chen Z. Schreiber H. Van Waes C. Oncogene. 2000; 19: 3477-3486Crossref PubMed Scopus (163) Google Scholar). Conversely, abolition of GRO1 via anti-GRO1-neutralizing antibody leads to reduction of tumor growth with decreased microvessel formation (15Wang D. Wang H. Brown J. Daikoku T. Ning W. Shi Q. Richmond A. Strieter R. Dey S.K. DuBois R.N. J. Exp. Med. 2006; 203: 941-951Crossref PubMed Scopus (299) Google Scholar). Furthermore, GRO1 was found to be a potent mediator of tumor-associated angiogenesis in colorectal and breast cancers (15Wang D. Wang H. Brown J. Daikoku T. Ning W. Shi Q. Richmond A. Strieter R. Dey S.K. DuBois R.N. J. Exp. Med. 2006; 203: 941-951Crossref PubMed Scopus (299) Google Scholar, 18Caunt M. Hu L. Tang T. Brooks P.C. Ibrahim S. Karpatkin S. Cancer Res. 2006; 66: 4125-4132Crossref PubMed Scopus (98) Google Scholar). However, how GRO1 expression is deregulated in malignant cells is still poorly understood. Transcriptional analysis revealed that the GRO1 promoter contains several cis-acting elements, including the ones recognized by nuclear factor κB (NF-κB), Sp1, and human CUT homeodomain protein/CCAAT displacement protein (19Nirodi C. Hart J. Dhawan P. Moon N.S. Nepveu A. Richmond A. J. Biol. Chem. 2001; 276: 26122-26131Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Indeed, NF-κB activity is found to be necessary for GRO1 expression in microvascular endothelial cells (20Karl E. Warner K. Zeitlin B. Kaneko T. Wurtzel L. Jin T. Chang J. Wang S. Wang C.Y. Strieter R.M. Nunez G. Polverini P.J. Nor J.E. Cancer Res. 2005; 65: 5063-5069Crossref PubMed Scopus (102) Google Scholar) and breast cancer cells (13Bachmeier B.E. Mohrenz I.V. Mirisola V. Schleicher E. Romeo F. Hohneke C. Jochum M. Nerlich A.G. Pfeffer U. Carcinogenesis. 2008; 29: 779-789Crossref PubMed Scopus (181) Google Scholar). Thus, GRO1 is regarded as one of NF-κB target genes (21Wood L.D. Richmond A. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus (74) Google Scholar). In the we that GRO1 is by endogenous mutant p53 and as a for mutant p53 gain of function. We that endogenous mutant p53 to the GRO1 promoter and that knockdown of mutant p53 inhibits GRO1 expression. In addition, of mutant R175H in p53-null HCT116 cells increases GRO1 expression. Interestingly, ectopic expression of GRO1 can rescue the proliferative defect in SW480 and MIA-PaCa-2 cells induced by knockdown of mutant p53. Conversely, knockdown of endogenous GRO1 inhibits cell proliferation and thus abrogates mutant p53 gain of function in SW480 cells. and p53, a p53 and a were of p53 or was performed by a that p53 the of one of was into and and the was as is a with a the R. R. 2002; PubMed Scopus Google Scholar). The into are and with the targeting shown in a that GRO1 one of targeting shown in was and into and and the was as or of GRO1 in cancer cells, a the GRO1 was an with the and the by and into and expression The were as and a that mutant a the of mutant was with a and a and by The was into and the as a that p53, a the of p53 was with a and a and by The was into and the was as The the of the was as S. Chen X. Oncogene. 2002; PubMed Scopus (61) Google Scholar). a the of the GRO1 a the GRO1 promoter to was SW480 cells with and The was into and by with and the was into The was as cell SW480 cancer cell MIA-PaCa-2 and carcinoma cell HCT116 and HCT116 were in with and cell in which targeting p53 is inducibly the of the were as W. Chen X. Cancer Res. 2007; PubMed Scopus Google Scholar). cell in which mutant p53 is inducibly knocked and GRO1 is was with into SW480 and MIA-PaCa-2 cells, which a by The p53 knockdown and cell were with and The of p53 knockdown and was by analysis with and cell that inducibly GRO1, was into SW480 cells, which a by The GRO1 cell were with and GRO1 was by analysis with cell that inducibly mutant was into cells, which a by The cell were with and mutant p53 was by analysis with and was cells which for analysis of human were analysis was performed to the analysis was performed as W. Chen X. Cancer Res. 2007; PubMed Scopus Google Scholar). The GRO1 was an The of was as a was a system was a the GRO1 was with the and the the was with the and the the was with the and the was as the and the The in the levels of GRO1, and to that of were a to in and for gene was was performed in to the of a of or that mutant p53 or p53, and of were into p53-null HCT116 cells. The in activity is a of the activity induced by mutant p53 by that induced by an The the of the in the promoter was as a (19Nirodi C. Hart J. Dhawan P. Moon N.S. Nepveu A. Richmond A. J. Biol. Chem. 2001; 276: 26122-26131Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). was performed as (17Loukinova E. Dong G. Enamorado-Ayalya I. Thomas G.R. Chen Z. Schreiber H. Van Waes C. Oncogene. 2000; 19: 3477-3486Crossref PubMed Scopus (163) Google Scholar, Y. M.A. H. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). cells, which were or induced to mutant p53 for were by for were and was to were with various The were by for and was by mutant p53 binding in the GRO1 including to to and to were by of were to with and with and and with and the to in the was performed with and in the promoter was to as a binding with and was performed as Y. M.A. H. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Biol. 2006; Google Scholar). The promoter to in the GRO1 was by with and The to in the which a known NF-κB binding was also by with and and as a binding The were to and to a protein of nuclear protein All of nuclear were were in cell of a 1 1 and the cells were in cell of a and various protein as and the was with a and The binding was performed by of nuclear protein of a of and of with various protein The was for with were by with and in the was for were on a and as with cells were with for with for with for and with and by with and and were also with to and with a of protein and in of was by and were and p53, and were Mol. Biol. 2006; Google Scholar). The of protein was as a or MIA-PaCa-2 cells in a were in the or of for and or with as for by one with to the The cells were in for the and with acid and with were performed in were by were and was of Mutant p53 GRO1 in SW480 and MIA-PaCa-2 in and in studies that in to loss of tumor-suppressing mutant p53 contributes to the malignant by additional including resistance to anticancer therapy and increased invasion and metastasis potential G. Lapi E. Strano S. Rinaldo C. Blandino G. Sacchi A. Oncogene. 2006; 25: 304-309Crossref PubMed Scopus (174) Google Scholar, T. Liu G. J.M. T. G. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). some mutant p53 is capable of transactivating genes in cell growth and such as c-MYC, MDR1, and M.W. He X. Wang J. Gu Z. Cleveland J.L. Zambetti G.P. Mol. Cell. Biol. 1998; 18: 3735-3743Crossref PubMed Scopus (176) Google Scholar, M.J. K.E. M.A. S. M. S. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, L. M. Rotter V. Oncogene. 2007; PubMed Scopus Google Scholar). However, it is whether these genes can be regulated by levels of mutant p53 in tumor cells. this, we utilized SW480 and MIA-PaCa-2 cell in which endogenous mutant p53 can be inducibly knocked by the of the promoter. p53 knockdown SW480 and MIA-PaCa-2 cell were Upon of p53, the levels of mutant p53 protein were Furthermore, to whether endogenous mutant p53 has a were to the of gene expression in SW480 and MIA-PaCa-2 cells, which were or induced to endogenous mutant p53. We found that GRO1 expression was mutant p53 and were performed and that the levels of GRO1 were decreased knockdown of mutant p53 in SW480 and and MIA-PaCa-2 and cells. The levels of were as a in whether of GRO1 in these cells is to mutant p53 p53 in HCT116 cells was knocked by p53 We found that the protein levels of p53 and its target the and with were by p53 but However, knockdown of p53 on the of GRO1 These that GRO1 is to be a target of mutant in SW480 cells and mutant in MIA-PaCa-2 cells. The NF-κB for Mutant p53 to GRO1 studies that GRO1 is an NF-κB target gene (21Wood L.D. Richmond A. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus (74) Google Scholar), and of the NF-κB activity inhibits GRO1 expression (13Bachmeier B.E. Mohrenz I.V. Mirisola V. Schleicher E. Romeo F. Hohneke C. Jochum M. Nerlich A.G. Pfeffer U. Carcinogenesis. 2008; 29: 779-789Crossref PubMed Scopus (181) Google Scholar, E. Warner K. Zeitlin B. Kaneko T. Wurtzel L. Jin T. Chang J. Wang S. Wang C.Y. Strieter R.M. Nunez G. Polverini P.J. Nor J.E. Cancer Res. 2005; 65: 5063-5069Crossref PubMed Scopus (102) Google Scholar). Interestingly, p53 was found to whereas mutant p53 was found to the expression and/or activity of the NF-κB pathway M.J. K.E. M.A. S. M. S. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar, A.C. S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, L. A. M. P. G. R. M. M. Strano S. Rotter V. Blandino G. M. Cancer Res. 2007; PubMed Scopus Google Scholar). Thus, we whether knockdown of mutant p53 leads to expression or activity of which GRO1 expression. this, was to the levels of and in SW480 cell and MIA-PaCa-2 cell that were or induced to mutant p53. We found that knockdown of mutant p53 on the of and in SW480 cells as as in MIA-PaCa-2 cells Consistent with this, we found that the and of protein were in SW480 and MIA-PaCa-2 cells with knockdown of mutant p53. the of mutant p53 and NF-κB to GRO1 expression, cells were with a specific of the NF-κB with knockdown of mutant p53. analysis was performed and that the of GRO1 expression, knockdown of mutant p53 GRO1 expression of with Thus, we that mutant p53 GRO1 of the NF-κB of Mutant p53 in p53-null HCT116 GRO1 that GRO1 is a target gene of mutant p53, GRO1 expression was in p53-null HCT116 cells that inducibly mutant R175H the promoter. in mutant R175H protein was induced a the of mutant p53 on GRO1 expression, analysis was performed and that the of GRO1 was increased expression of mutant R175H the was performed and that the of GRO1 was increased ectopic expression of mutant p53 and by the of a we the of p53 on GRO1 expression in p53-null HCT116 cells. We found that p53 was and as by the of However, of p53 on the of GRO1 We that the ability of exogenous mutant p53 to GRO1 in p53-null HCT116 cells is potent with with that of endogenous mutant p53 in SW480 and MIA-PaCa-2 cell is endogenous and exogenous p53 can be and thus have activity C. 1996; 10: PubMed Scopus Google Scholar). we that GRO1 is to be a mutant p53 target Mutant p53 to and the GRO1 whether GRO1 is a target gene of mutant p53 in we to identify a potential binding for by mutant p53. a has for p53, such a for mutant p53 has Thus, a was performed with of to a large the GRO1 promoter to were SW480 cells, which were or induced to mutant p53, and with antibody or an as a In addition, potential binding of mutant p53 to the and was also We that a in the GRO1 promoter to was in mutant but mutant and The between and in the GRO1 promoter was mutant whereas the between and was and antibody GRO1 promoter was In addition, the in the gene and the promoter were found to with mutant p53 and In we performed a to the between mutant p53 and the GRO1 promoter in the GRO1 promoter to on and nuclear protein SW480 cells or induced to mutant p53. The GRO1 promoter also contains a NF-κB binding to P. Richmond A. J. Leukocyte Biol. 2002; 72: 9-18PubMed Google Scholar). a was to as a Indeed, we found that protein was in SW480 cells of mutant p53 knockdown and In addition, we found that mutant p53 was by the GRO1 promoter in SW480 cells with mutant p53 However, of p53, mutant p53 was Furthermore, mutant p53 and were the promoter was 1 and a was performed to whether the GRO1 promoter is to mutant p53. this, a GRO1 promoter to with which mutant p53 was found to by was into the The was The was into p53-null HCT116 cells with a or a that mutant We found that the activity for was increased by mutant but p53 However, the the of the promoter was to p53 but Furthermore, the activity was to mutant or p53 and These are with the by and However, the for mutant p53 in the GRO1 promoter to be which is the of of GRO1 the by of Mutant p53 in SW480 and MIA-PaCa-2 whether GRO1 is to mediate mutant p53 gain of we SW480 and MIA-PaCa-2 cell in which GRO1 is overexpressed with knockdown of mutant p53. SW480 cell and and MIA-PaCa-2 cell and were for Upon of p53, the levels of p53 protein were In addition, GRO1 was found to be in one SW480 cell and in MIA-PaCa-2 cell and GRO1 a formation was performed to the of GRO1 on mutant p53 gain of function. We that knockdown of mutant p53 in SW480 cells and and in MIA-PaCa-2 cells and the formation ability was of with In expression of GRO1 in SW480 and and in MIA-PaCa-2 and knockdown of mutant p53 on formation and with of that mutant p53 is for cell proliferation of SW480 and MIA-PaCa-2 cells, and ectopic expression of GRO1, as a target of mutant p53, is to for knockdown of mutant p53. of GRO1 and to mutant p53 has in cell and cell resistance to by GRO1 expression, we whether ectopic expression of GRO1 is capable of mutant p53 we SW480 cell in which GRO1 can be inducibly the of the promoter. Upon with GRO1 protein was inducibly formation that expression of GRO1, the ability of SW480 cells was increased and In addition, expression of GRO1, the ability of SW480 cells to proliferate with was also increased and These that of GRO1 in SW480 cells is to cell proliferation and cancer cells to anticancer GRO1 for Mutant p53 of whether GRO1 is for mutant p53 gain of we SW480 cell in which endogenous GRO1 can be inducibly knocked by cell were for We that of GRO1, the levels of GRO1 protein and were we the ability of SW480 cells GRO1 We that cell proliferation was by knockdown of GRO1 and In addition, the of SW480 cells to was also increased as the number and the of were decreased GRO1 knockdown and and our that one mechanism by which mutant p53 promotes cell proliferation and in cancer cells is by of GRO1 expression. GRO1 and p53 are known to a with cell growth G. Lapi E. Strano S. Rinaldo C. Blandino G. Sacchi A. Oncogene. 2006; 25: 304-309Crossref PubMed Scopus (174) Google Scholar, S. A. Cancer 2007; PubMed Scopus Google Scholar, Y. J. Liu Q. R. P. M. S. Carcinogenesis. 2005; PubMed Scopus Google Scholar). of GRO1 and p53, which frequently in leads to cell growth and cancer development and G. Lapi E. Strano S. Rinaldo C. Blandino G. Sacchi A. Oncogene. 2006; 25: 304-309Crossref PubMed Scopus (174) Google Scholar, Y. J. Liu Q. R. P. M. S. Carcinogenesis. 2005; PubMed Scopus Google Scholar). GRO1 and mutant p53 are still regarded as However, evidence to a and between the CXC chemokine and p53. p53 and expression P. Jr., L. H. Oncogene. 2007; PubMed Scopus Google Scholar) and thus cell migration and Here, we that knockdown of mutant p53 whereas ectopic expression of mutant p53 GRO1 expression. In addition, the GRO1 promoter contains a that with and is to mutant p53. Interestingly, ectopic expression of GRO1 can rescue the proliferative defect induced by knockdown of mutant p53 in SW480 and MIA-PaCa-2 cells. Conversely, knockdown of endogenous GRO1 inhibits cell proliferation and abrogates mutant p53 gain of function in SW480 cells. Thus, targeting GRO1 for cancer therapy would be applicable to a large portion of human tumors with mutant p53, but exploration of GRO1 as a potential target should take into the mutation status of p53. to its potent GRO1 has to its by NF-κB A. M. R. J. Google Scholar). NF-κB was found to be one of the for GRO1 expression M.E. Richmond A. Oncogene. 2006; 25: PubMed Scopus Google Scholar, L.D. Richmond A. Res. 1995; PubMed Scopus Google Scholar). The GRO1 promoter was found to an NF-κB binding with a and an mutant p53 was found to expression for its gain of function M.J. K.E. M.A. S. M. S. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar), it is that mutant p53 of GRO1 be by However, we that knockdown of mutant p53 has on expression levels of NF-κB and and of the that the mutant p53 was found to with and the GRO1 it is to that GRO1 is a target of mutant p53. Consistent with a that in cells that mutant and the of GRO1 was increased G. C. L. B. Chen L. P. A. H. 2008; PubMed Scopus Google Scholar), it is whether the increased expression is to mutant p53, or In our evidence that GRO1, which is known to a in mutant p53 gain of function. Thus, targeting GRO1 have effects on of tumors with mutant p53.