Thomas A. Langan, Ph.D.

Professor of Pharmacology

Department of Pharmacology
University of Colorado Health Sciences Center
Campus Box C236
4200 East Ninth Avenue
Denver, Colorado 80262

Phone: 303.315.8965
Thomas.Langan@uchsc.edu

EDUCATION/EXPERIENCE

Research Interests

Our laboratory has maintained a long term interest in the role of protein phosphorylation in regulation of functions in the cell nucleus, including control of progression through the cell cycle and transcriptional regulation.

Research is currently focused on assessment of the defects in cell cycle regulatory components found in lung, breast and ovarian cancer cells and tissues, in particular the overexpression of G1 type cyclins and/or underexpression of the tumor suppressors retinoblastoma protein Rb and the cyclin-dependent kinase inhibitor, p16, which are known to participate in G1 cyclin-mediated cell cycle regulation at the G1/S boundary. In breast cancer the defects in regulation at this point in the cell cycle were found to fall into two classes: 1) failure to express the Rb tumor suppressor protein in the presence of extremely low or undetectable levels of cyclin D1, and 2) failure to express p16 inhibitor protein in the presence of normal levels of Rb, accompanied by expression of normal or above normal levels of cyclin D1. These findings are consistent with the general observations made in a large number of laboratories that most cancer cells have defects of one kind or another in cell cycle regulation at the G1/S boundary, and have led to the conclusion that the development of such defects is an obligatory step in the progression of cells to the malignant state.

However, in most ovarian cancer cells, and in a subset of breast cancer cells, we have found that normal or greater than normal amounts of p16 are expressed together with Rb and cyclin D1, calling into question the generality of the conclusion that a breakdown of cell cycle regulation at the G1 boundary is a hallmark of cancer cells. We have now shown that these apparently normal ovarian and breast cancer cells are actually defective in their ability to respond to cell cycle regulation by p16 inhibition. The fact that cancer cells can be defective in cell cycle regulation by mechanisms in addition to the loss of p16 or Rb expression makes it more likely that the vast majority, if not all, cancer cells harbor G1/S cell cycle regulatory defects, and that the development of such defects is a truly obligatory step in the development of cancer. We are currently investigating the mechanisms by which these ovarian and breast cancer cells escape growth inhibition by p16. Data obtained so far indicate that at least two distinct mechanisms occuring in different cell lines are involved, one resulting in an inability of massively elevated levels of ectopic functional p16 to inhibit Rb phosphorylation, and a second allowing uninhibited cell growth to occur in the presence of hypophosphorylated Rb.

Selected Publications

• Grimison, B., Langan, T.A. and Sclafani, R.A.: p16Ink4a tumor suppressor function in lung cancer cells involves cyclin-dependent kinase 2 inhibition by Cip/Kip protein redistribution. Cell Growth Differentiation, 11, 507-515 (2000). [Abstract]

• Todd, M.C., Sclafani, R.A. and Langan, T.A.: Ovarian cancer cells that coexpress endogenous Rb and p16 are insenstitive to overexpression of functional p16 protein. Oncogene 19, 258-264 (2000). [Abstract]

• Shellman, Y.G., Svee, E., Sclafani, R.A. and Langan, T.A.: Identification and characterization of individual cyclin-dependent kinase complexes from S. cerevisae. Yeast 15, 295-309 (1999). [Abstract]

• Groshung, S.D., Owen, G.I., Grimison, B., Schauer, I.E., Todd, M.C., Langan, T.A., Sclafani, R.A., Lange, C.A. and Horwitz, K.B.: Biphasic regulation of breast cancer cell growth by progesterone: Role of cyclin-dependent kinase inhibitors, p21 and p27Kip1. Mol. Endocrinol., 11, 1593-1607 (1997). [Abstract]

Bibliography