Heat shock proteins in human cancer The heat shock proteins (hsp) are ubiquitous molecules induced in cells exposed to sublethal heat shock, present in all living cells, and highly conserved during evolution. Their function is to protect cells from environmental stress damage by binding to par- tially denatured proteins, dissociating protein aggregates, to regulate the correct fold- ing, and to cooperate in transporting newly synthesized polypeptides to the target organelles. The molecular chaperones are involved in numerous diseases, including cancer, revealing changes of expression. In this review, we mainly describe the rela- tionship of hsp expression with human cancer, and discuss what is known about their post-translational modifications according to malignancies. Keywords: Heat shock proteins / Two-dimensional electrophoresis / Post-translational modifica- tion / Cancer / Review EL 3863 Review Cecilia Sarto 1 Pierre-Alain Binz 2, 3 Paolo Mocarelli 1 1 University Department of Clinical Pathology, Desio Hospital, Desio-Milan, Italy 2 Swiss Institute of Bioinformatics, Geneva, Switzerland 3 Laboratoire Central de Chimie Clinique, Hôpital Cantonal de Genve, Geneva, Switzerland Contents 1 Introduction ...................... 1218 2 Molecular structure and gene regulation ... 1219 2.1 Molecular structure ................. 1219 2.2 Gene structure .................... 1220 2.3 Regulation ....................... 1220 3 Functions ........................ 1220 3.1 Hsp90 family ...................... 1220 3.2 Hsp70 family ...................... 1221 3.3 Hsp60 family ...................... 1222 3.4 Small hsp ........................ 1222 4 Expression in cancer ................ 1222 5 Perspectives ...................... 1224 6 References ....................... 1224 1 Introduction The heat shock or stress-induced proteins (hsp) are a group of proteins induced in cells exposed to sublethal heat shock, present in all living cells, and highly con- served during evolution. In fact, human and bacterial stress proteins show a sequence similarity as high as 50%. These proteins are found in nearly every cellular compartment, including cytosol, mitochondria, nucleus, nucleolus, endoplasmic reticulum, and outer and inner membranes. They function as molecular chaperones to protect cells from environmental stress damage by bind- ing to partially denatured proteins, dissociating protein aggregates, and regulating correct folding [1]. In addition, they cooperate in transporting newly synthesized poly- peptides to the target organelles for final packaging, deg- radation or repair, and constitute a major factor in the pro- tein quality control mechanism as a triage system [2]. They are inducible in physiological conditions such as cycle cell division, apoptosis, growth factor activity, cell differentiation, tissue development, and hormonal stimu- lation. Although a number of molecular chaperones are constitutively expressed, many of them are induced by heat shock and other inducing stimuli, including exposure to amino acid analogs [3, 4], glucose analogs [5], heavy metals [6], protein kinase C (PKC) stimulators [7], ische- mia, sodium arsenite [8], microbial infections, nitric oxide, hormones, and antibiotics, infections, and cancer. The hsp cannot be settled according to their specific cellu- lar functions but they can be classified by their electropho- retic characteristics into three groups, with an increasing number of members in each group. The hsp of the first group have molecular masses of 60, 70, 90, and 110 kDa and are also expressed in the absence of heat shock. Hsp70 and hsp90 are present in all organisms, whereas hsp110 is found mainly in mammalian cells. A second group is composed of hsp induced by glucose deprivation and includes glucose-regulated proteins (grp) 34, 47, 56, 76, 78, 94, and 174 kDa [9]. The small molecular mass hsp (shsp) belong to a third group, and include hsp27, ubiquitin, and alpha-crystallin. The first report on hsp ap- peared in 1962 [10], and from then, genomic studies have Correspondence: Dr. Cecilia Sarto, University Department of Clinical Pathology, Desio Hospital, Via mazzini 1, I-20033 Desio, Milan, Italy E-mail: sarto@uds.unimib.it Fax: +39-362-383464 Abbreviations: grp, glucose-regulated protein; hsp, heat shock protein(s); PKC, protein kinase C; shsp, small molecular mass hsp; TNF, tumor nercrosis factor 1218 Electrophoresis 2000, 21, 1218±1226  WILEY-VCH Verlag GmbH, 69451 Weinheim, 2000 0173-0835/00/0606-1218 $17.50+.50/0