ELSEVIER Cancer Letters 107 (1996) 193-198 CANCER LETTERS Sterol dependent LDL-receptor gene transcription in lymphocytes from normal and CML patients Rajeev Gael”, S. Vannab, D. Kaula>* “Molecular Biology Unit, Department of Experimental Medicine and Eioterhnology,Chandigarh 160 012, India bDeportment of Internal Medicine, Postgraduate Institute of Medical Education and Research,Chandigarh 160 012, India Received 17 January 1996; revision received 11 June 1996; accepted 13 June 1996 Abstract Sterol regulatory element (SRE) has been recognized to regulate various key genes coding for especially low density lipoprotein (LDL)-receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase known to play a crucial role in the cholesterol feedback mechanism. The deranged cholesterol feedback mechanism has been widely recognised in initiation as well as progression of various types of cancers including chronic myeloid leukaemia (CML). Consequently, the present study was addressed to understand this phenomenon and revealed the existence of a unique 47 kDa protein factor having affinity for this SRE sequence in lymphocytes from normal subjects as well as its absence in lympho- cytes from untreated CML patients. However, this factor appeared when the CML patients achieved complete haematological remission (CHR) through a-interferon therapy. Further, an inverse relationship was also observed between sterol modulated LDL-receptor gene transcription and the binding affinity of this 47 kDa factor to the SRE sequence. Based upon these results we propose that o-interferon through its receptor initiates phosphatidic acid dependent signalling which in turn regulates the affinity of 47 kDa sterol regulatory element binding factor as well as LDL-receptor gene transcription in lymphocytes from CML patients. Keywords: LDL-receptor gene; Transcription; Sterol; Lymphoc 1, tes; Interferon-o; Leukaemia 1. Introduction The consistency with which the loss of the choles- terol feedback system together with over expression of low density lipoprotein (LDL) receptorsthat occurs in malignant cells [l-3] as well as the findings that these defects precede the appearance of cancer under premalignant conditions [4] support the hypothesis that deregulated LDL-receptor expressions coupled with cholesterogenesis might be involved in the * Corresponding author. early stages of carcinogenesis [3]. This paradox is alsoexhibited by the lymphocytes from chronic mye- loid leukemic patients [l]. Sterol regulatory element (SRE) has been recognised to be responsible for the regulation of various genes coding for LDL receptor aswell as two key enzymes, 3-hydroxy-3-methylglu- taryl coenzyme A (HMG-CoA) reductase and HMG- CoA synthase involved in the cholesterogenesis path- way [5]. The SRE which is present in the promoter region of these genescontains the consensus octarm- cleotide sequences GTG (G/C) GGTG [6] and the point mutations in SRE have been shown to reduce 03043835/96/$12.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII SO304-3835(96)04355-8