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Clone 10d/BM28 (CDCL1), an Early S-Phase Protein, Is an Important Growth Regulator of Melanoma¹

Department of Surgery, Division of Surgical Oncology, Laboratory of Biological Cancer Therapy [R. A. S., P. L., P. S. G., T. J. E.], and Department of Medicine, Division of Dermatology, Harvard Skin Disease Research Center [S. S.], Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Retinoic acid (RA) induces growth arrest and differentiation of many different tumor cells. RA activates RA receptors, which function as ligand-dependent transcriptional modulators. S91 murine melanoma cells stop proliferating and then reversibly differentiate into a melanocytic cell type after the administration of RA. The genetic changes that take place during this process serve as an excellent model for the etiology of melanoma. The use of subtractive hybridization techniques yielded several differentially expressed cDNAs that are associated with RA-induced growth arrest. One clone, cyclin D1, is repressed and is probably a differentiation marker. Two other cDNAs represent novel, RA-inducible genes. Expression of another cDNA, clone 10d, is strongly down-regulated. It is the homologue of the human gene BM28 (CDCL1) that is indispensable for entry into S phase and cell division. S91 cells that are permanently transfected with a plasmid that constitutively expresses clone 10d become significantly more resistant to RA, suggesting that repression of this gene is a critical event in RA-induced growth arrest. The use of reverse transcription-PCR for the detection of expression in human melanoma in vitro was performed to study the potential role of clone 10d/BM28 in this disease. It is expressed in 80% of melanoma cell lines but is virtually undetectable in primary melanocytes. The expression of BM28 is not regulated by RA in human, RA-resistant melanoma cells. These results suggest that clone 10d/BM28 functions as an important tumor cell growth promoter. The regulation of clone 10d may be directly mediated by RA receptors, and escape from negative regulation may, thus, contribute to the etiology of melanoma.

¹ This work was supported by American Cancer Society Grant CNE-86193 (to R. A. S.).

² To whom requests for reprints should be addressed, at Department of Surgery, Division of Surgical Oncology, Brigham and Women's Hospital, Thorn 303, 75 Francis Street, Boston, MA 02115.

Received 5/19/97. Accepted 9/18/97.

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