Spermatocytes, the most sensitive male germ cells to heatinduced apoptosis, do not respond to hyperthermia by inducing heat shock proteins (HSPs), including HSP70i, which has been previously shown to confer resistance to apoptosis in somatic cells. To dissect the mechanism of heat-induced apoptosis and to determine if we could protect spermatocytes by expressing HSP70i, we engineered transgenic mice that express in spermatocytes constitutively active heat shock transcription factor (HSF)1. Such HSF1 expression did not lead to transcription of inducible Hsp70 genes, but instead induced caspase-dependent apoptosis that mimicked heat shock-induced death of spermatogenic cells. Both mitochondria-dependent and death receptor-dependent pathways appear to be involved in such HSF1-induced apoptosis: the levels of Bcl-2 family proteins became increased, p53 protein accumulated and expression levels of caspase-8 and deathreceptor-interacting proteins (including Fas-associated death domain protein and TNF receptor associated death domain protein) became elevated. Surprisingly, the constitutive spermatocyte-specific expression of HSP70i in doubletransgenic males did not protect against such HSF1-induced apoptosis.

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BackgroundThe molecular mechanisms driving the papillary thyroid carcinoma (PTC) are still poorly understood. The most frequent genetic alteration in PTC is the BRAFV600E mutation–its impact may extend even beyond PTC genomic profile and influence the tumor characteristics and even clinical behavior.MethodsIn order to identify BRAF-dependent signature of early carcinogenesis in PTC, a transgenic mouse model with BRAFV600E-induced PTC was developed. Mice thyroid samples were used in microarray analysis and the data were referred to a human thyroid dataset.ResultsMost of BRAF(+) mice developed malignant lesions. Nevertheless, 16% of BRAF(+) mice displayed only benign hyperplastic lesions or apparently asymptomatic thyroids. After comparison of non-malignant BRAF(+) thyroids to BRAF(−) ones, we selected 862 significantly deregulated genes. When the mouse BRAF-dependent signature was transposed to the human HG-U133A microarray, we identified 532 genes, potentially indicating the BRAF signature (representing early changes, not related to developed malignant tumor). Comparing BRAF(+) PTCs to healthy human thyroids, PTCs without BRAF and RET alterations and RET(+), RAS(+) PTCs, 18 of these 532 genes displayed significantly deregulated expression in all subgroups. All 18 genes, among them 7 novel and previously not reported, were validated as BRAFV600E-specific in the dataset of independent PTC samples, made available by The Cancer Genome Atlas Project.ConclusionThe study identified 7 BRAF-induced genes that are specific for BRAF V600E-driven PTC and not previously reported as related to BRAF mutation or thyroid carcinoma: MMD, ITPR3, AACS, LAD1, PVRL3, ALDH3B1, and RASA1. The full signature of BRAF-related 532 genes may encompass other BRAF-related important transcripts and require further study.

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HSF1 (Heat Shock transcription Factor 1) is the main transcription factor activated in response to proteotoxic stress. Once activated, it induces an expression of heat shock proteins (HSPs) which enables cells to survive in suboptimal conditions. HSF1 could be also activated by altered kinase signaling characteristic for cancer cells, which is a probable reason for its high activity found in a broad range of tumors. There is rapidly growing evidence that HSF1 supports tumor initiation and growth, as well as metastasis and angiogenesis. It also modulates the sensitivity of cancer cells to therapy. Functions of HSF1 in cancer are connected with HSPs’ activity, which generally protects cells from apoptosis, but also are independent of its classical targets. HSF1-dependent regulation of non-HSPs genes plays a role in cell cycle progression, glucose metabolism, autophagy and drug efflux. HSF1 affects the key cell-survival and regulatory pathways, including p53, RAS/MAPK, cAMP/PKA, mTOR and insulin signaling. Although the exact mechanism of HSF1 action is still somewhat obscure, HSF1 is becoming an attractive target in anticancer therapies, whose inhibition could enhance the effects of other treatments.