FUNCTIONAL AND TRANSCRIPTIONAL REGULATION OF STRESS PROTEINS

In response to stress factors such as metal ions, UV irradiation, and reactive oxygen species, cells synthesize a class of specialised proteins, known as stress proteins. These proteins allow the organism to regain normal function and overcome threats to its integrity. Cells possess mechanisms controlling the synthesis of stress proteins. The identification and characterization of the cellular regulatory factors involved in the mechanisms of stress signal transduction into transcriptional activity is essential in determining the molecular and genetic basis of cellular stress factor responses. Cellular responses to stress factors partially overlap with normal growth responses and have common nuclear targets. The existence of connections between the activation of stress genes and general signal transduction pathways suggests an integration between stress response and cellular growth control. A better understanding of the mechanism controlling stress-regulated transcription may increase our knowledge of normal growth control mechanisms. To identify stress regulatory proteins, we are studying the regulatory protein(s) governing metal-regulated transcription in the mouse metallothionein-1 (MT) gene. MTs are small cysteine-rich, metal-binding proteins. MT genes are inducible at the transcriptional level by a variety of stress factors, and thus represent a good model system to study the molecular bases of genetic control of the defense mechanisms activated by stress factors. The objective of this project is to characterize the signaling mechanisms governing metal-regulated transcription, and to determine whether these mechanisms are activated during normal growth control.

Another aspect of our research involves MT-3, a new MT gene family member which inhibits survival of rat neurons in culture, and which is down-regulated in the brain of some Alzheimer's disease (AD) patients. It has been suggested that MT-3 is involved in AD pathological processes. While MT-3 was reported to be brain-specific, we found that it is also expressed in the testis, the prostate, the ovaries, and the uterus. In the prostate, MT-3 biosynthesis appears to be upregulated by androgens, and MT-3 can inhibit steroid secretion in granulosa cells in primary culture. The exact function of MT-3 in the brain and the reproductive system is presently unknown. Growth factors play important roles in the regulation of the brain, the testis, the ovaries, and the prostate physiologies. Imbalances between growth-inhibitory and growth-stimulatory factors results in abnormal growth and disease. MT-3 may be a new important component of cellular homeostasis in normal physiological or neoplastic processes, and understanding its function and regulation may be of major importance in cancerology and endocrinology. The objective of this project is to examine the function and regulation of MT-3 both in the reproductive system and prostate and ovarian cancers, and to characterize MT-3 transcriptional regulation.

These projects are supported by NSERC.

St-Jacques E, Guay J, Wirtanen L, Huard V, Stewar, G, Séguin C (1997) Cloning of a complementary DNA encoding an Ambystoma mexicanum metallothionein, AmMT, and expression of the gene during early development. DNA Cell Biol 17: 83-91.

Wirtanen L, Huard V, Séguin C (1997) Molecular cloning of a nuclear orphan receptor (aDOR1) closely related to TR2-11 from neurulating Ambystoma mexicanum embryos. Differentiation 62: 159-170

Labbé S, Simard C, Séguin C (1998) Metallothionein gene regulation in mouse cells. In: Metal ions in gene regulation (Ed. S. Silver and W. Walden) chapitre 9 231-2494, Chapman & Hall, New York.