Logo of amjpatholAmerican Journal of Pathology For AuthorsAmerican Journal of Pathology SubscribeAmerican Journal of Pathology SearchAmerican Journal of Pathology Current IssueAmerican Journal of Pathology About the JournalAmerican Journal of Pathology
Am J Pathol. Dec 1996; 149(6): 1813–1822.
PMCID: PMC1865341

Cyclin kinase inhibitor p21WAF1/CIP1 in malignant melanoma: reduced expression in metastatic lesions.


Immunohistochemical analysis of the expression of the cyclin kinase inhibitor p21WAF1/CIP1 in a panel of primary and metastatic human melanocytic tumors was performed. It was found that, independent of the p53 status, approximately 30% of the primary melanomas and 40% of the metastases completely lacked expression of this cell cycle inhibitor. Some tumors were also analyzed by Northern blotting, and in most of the cases a consistant correlation between mRNA and protein expression was observed. In four benign nevi studied, WAF1/CIP1 mRNA was expressed whereas the protein was not detected, suggesting a post-transcriptional regulation of the inhibitor in these cases. In superficial spreading melanomas, a significant correlation between protein expression and tumor thickness was found, with thin lesions showing low protein levels. Interestingly, by comparing primary and metastatic specimens obtained from the same patient, a reduction in p21WAF1/CIP1 antibody staining was observed in the latter, probably reflecting a more aggressive phenotype of the metastases. In conclusion, our results demonstrate the complexity in the relationship between p21WAF1/CIP1 expression and tumor phenotype and furthermore suggest that aberrant expression of the cyclin-dependent kinase inhibitor may be of importance in the development and progression of sporadic malignant melanoma.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hunter T, Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994 Nov 18;79(4):573–582. [PubMed]
  • Kamb A. Cell-cycle regulators and cancer. Trends Genet. 1995 Apr;11(4):136–140. [PubMed]
  • Xiong Y, Zhang H, Beach D. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell. 1992 Oct 30;71(3):505–514. [PubMed]
  • Zhang H, Xiong Y, Beach D. Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes. Mol Biol Cell. 1993 Sep;4(9):897–906. [PMC free article] [PubMed]
  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993 Dec 16;366(6456):701–704. [PubMed]
  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. [PubMed]
  • Waga S, Hannon GJ, Beach D, Stillman B. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature. 1994 Jun 16;369(6481):574–578. [PubMed]
  • Li R, Waga S, Hannon GJ, Beach D, Stillman B. Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Nature. 1994 Oct 6;371(6497):534–537. [PubMed]
  • Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, Dobrowolski S, Bai C, Connell-Crowley L, Swindell E, et al. Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell. 1995 Apr;6(4):387–400. [PMC free article] [PubMed]
  • Zhang H, Hannon GJ, Beach D. p21-containing cyclin kinases exist in both active and inactive states. Genes Dev. 1994 Aug 1;8(15):1750–1758. [PubMed]
  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. [PubMed]
  • Eastham JA, Hall SJ, Sehgal I, Wang J, Timme TL, Yang G, Connell-Crowley L, Elledge SJ, Zhang WW, Harper JW, et al. In vivo gene therapy with p53 or p21 adenovirus for prostate cancer. Cancer Res. 1995 Nov 15;55(22):5151–5155. [PubMed]
  • Chen YQ, Cipriano SC, Arenkiel JM, Miller FR. Tumor suppression by p21WAF1. Cancer Res. 1995 Oct 15;55(20):4536–4539. [PubMed]
  • Di Leonardo A, Linke SP, Clarkin K, Wahl GM. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 1994 Nov 1;8(21):2540–2551. [PubMed]
  • Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res. 1994 Mar;211(1):90–98. [PubMed]
  • Steinman RA, Hoffman B, Iro A, Guillouf C, Liebermann DA, el-Houseini ME. Induction of p21 (WAF-1/CIP1) during differentiation. Oncogene. 1994 Nov;9(11):3389–3396. [PubMed]
  • Jiang H, Lin J, Su ZZ, Collart FR, Huberman E, Fisher PB. Induction of differentiation in human promyelocytic HL-60 leukemia cells activates p21, WAF1/CIP1, expression in the absence of p53. Oncogene. 1994 Nov;9(11):3397–3406. [PubMed]
  • Shao ZM, Dawson MI, Li XS, Rishi AK, Sheikh MS, Han QX, Ordonez JV, Shroot B, Fontana JA. p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. Oncogene. 1995 Aug 3;11(3):493–504. [PubMed]
  • Albino AP, Fountain JW. Molecular genetics of human malignant melanoma. Cancer Treat Res. 1993;65:201–255. [PubMed]
  • Trent JM, Stanbridge EJ, McBride HL, Meese EU, Casey G, Araujo DE, Witkowski CM, Nagle RB. Tumorigenicity in human melanoma cell lines controlled by introduction of human chromosome 6. Science. 1990 Feb 2;247(4942):568–571. [PubMed]
  • Vidal MJ, Loganzo F, Jr, de Oliveira AR, Hayward NK, Albino AP. Mutations and defective expression of the WAF1 p21 tumour-suppressor gene in malignant melanomas. Melanoma Res. 1995 Aug;5(4):243–250. [PubMed]
  • Jiang H, Lin J, Su ZZ, Herlyn M, Kerbel RS, Weissman BE, Welch DR, Fisher PB. The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells. Oncogene. 1995 May 4;10(9):1855–1864. [PubMed]
  • Flørenes VA, Oyjord T, Holm R, Skrede M, Børresen AL, Nesland JM, Fodstad O. TP53 allele loss, mutations and expression in malignant melanoma. Br J Cancer. 1994 Feb;69(2):253–259. [PMC free article] [PubMed]
  • Flørenes VA, Holm R, Fodstad O. Accumulation of p53 protein in human malignant melanoma. Relationship to clinical outcome. Melanoma Res. 1995 Jun;5(3):183–187. [PubMed]
  • Herlyn M, Thurin J, Balaban G, Bennicelli JL, Herlyn D, Elder DE, Bondi E, Guerry D, Nowell P, Clark WH, et al. Characteristics of cultured human melanocytes isolated from different stages of tumor progression. Cancer Res. 1985 Nov;45(11 Pt 2):5670–5676. [PubMed]
  • Herlyn M. Human melanoma: development and progression. Cancer Metastasis Rev. 1990 Sep;9(2):101–112. [PubMed]
  • Hsu SM, Raine L, Fanger H. A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying polypeptide hormones with radioimmunoassay antibodies. Am J Clin Pathol. 1981 May;75(5):734–738. [PubMed]
  • Cattoretti G, Becker MH, Key G, Duchrow M, Schlüter C, Galle J, Gerdes J. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992 Dec;168(4):357–363. [PubMed]
  • Maelandsmo GM, Flørenes VA, Hovig E, Oyjord T, Engebraaten O, Holm R, Børresen AL, Fodstad O. Involvement of the pRb/p16/cdk4/cyclin D1 pathway in the tumorigenesis of sporadic malignant melanomas. Br J Cancer. 1996 Apr;73(8):909–916. [PMC free article] [PubMed]
  • Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. [PMC free article] [PubMed]
  • el-Deiry WS, Tokino T, Waldman T, Oliner JD, Velculescu VE, Burrell M, Hill DE, Healy E, Rees JL, Hamilton SR, et al. Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues. Cancer Res. 1995 Jul 1;55(13):2910–2919. [PubMed]
  • Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994 Jul 1;54(13):3391–3395. [PubMed]
  • Jung JM, Bruner JM, Ruan S, Langford LA, Kyritsis AP, Kobayashi T, Levin VA, Zhang W. Increased levels of p21WAF1/Cip1 in human brain tumors. Oncogene. 1995 Nov 16;11(10):2021–2028. [PubMed]
  • Barboule N, Mazars P, Baldin V, Vidal S, Jozan S, Martel P, Valette A. Expression of p21WAF1/CIP1 is heterogeneous and unrelated to proliferation index in human ovarian carcinoma. Int J Cancer. 1995 Nov 27;63(5):611–615. [PubMed]
  • Pontén F, Berne B, Ren ZP, Nistér M, Pontén J. Ultraviolet light induces expression of p53 and p21 in human skin: effect of sunscreen and constitutive p21 expression in skin appendages. J Invest Dermatol. 1995 Sep;105(3):402–406. [PubMed]
  • Elbendary A, Berchuck A, Davis P, Havrilesky L, Bast RC, Jr, Iglehart JD, Marks JR. Transforming growth factor beta 1 can induce CIP1/WAF1 expression independent of the p53 pathway in ovarian cancer cells. Cell Growth Differ. 1994 Dec;5(12):1301–1307. [PubMed]
  • Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5545–5549. [PMC free article] [PubMed]
  • Zhang W, Grasso L, McClain CD, Gambel AM, Cha Y, Travali S, Deisseroth AB, Mercer WE. p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. Cancer Res. 1995 Feb 1;55(3):668–674. [PubMed]
  • Reed JA, Loganzo F, Jr, Shea CR, Walker GJ, Flores JF, Glendening JM, Bogdany JK, Shiel MJ, Haluska FG, Fountain JW, et al. Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression. Cancer Res. 1995 Jul 1;55(13):2713–2718. [PubMed]
  • Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS, 3rd, Johnson BE, Skolnick MH. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994 Apr 15;264(5157):436–440. [PubMed]
  • Xiao S, Li D, Corson JM, Vijg J, Fletcher JA. Codeletion of p15 and p16 genes in primary non-small cell lung carcinoma. Cancer Res. 1995 Jul 15;55(14):2968–2971. [PubMed]
  • Nasmyth K, Hunt T. Cell cycle. Dams and sluices. Nature. 1993 Dec 16;366(6456):634–635. [PubMed]
  • Pines J. Arresting developments in cell-cycle control. Trends Biochem Sci. 1994 Apr;19(4):143–145. [PubMed]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...